Um, today, im going to talk about a topic on the using proteins as a drug target for cholera in fashion. It is. And. Okay, um, I think we are now about 1 or 2 years post covert, okay? And the virus that caused the um the cold in 19, it's called, especially belongs to one of the so called coral coral arrivals. So this is actually the structure of the core rivals. And basically, you've got you've got a lot of all these uh, like aa spike protein, which is actually sticking out from the surface of the virus. Yeah. So under the uh, electron microscope is look like a crown. That's why it is called corner linus. Um, and then, yeah, because this and then within you've got a lot of all the others membrane, protein and things like that.
嗯，今天我要讲的话题是用蛋白质作为时尚界霍乱的药物靶点。这是。和。好吧，嗯，我想我们现在已经是秘密行动后大约一两年了，好吗？导致19年感冒的病毒，它被称为，特别属于所谓的珊瑚到达者之一。所以这实际上就是核心竞争对手的结构。基本上，你有很多这些呃，比如刺突蛋白，它实际上是从病毒表面伸出的。是的。所以在呃电子显微镜下看起来就像一顶王冠。这就是为什么它被称为角线。嗯，然后，是的，因为这个，然后在你体内有很多其他的膜、蛋白质和类似的东西。

And inside the coronavirus, it is actually the genetic information is arna okay, it's not dna it's the genetic information that are stored within the virus. You say, all right, so it's also called a rna virus. And virus is actually very complicated in the sense that is about diversity. And this virus has a so called a single strand, which is the the opposite strap, which is the the the same strength, is a single strand of rna virus. So, and yeah, you have a spike proteins taking on. It was an apple protein. Also, if you've got like a membrane limit by layer, and there's also a membrane protein here and there on surface of the process. Thank you.
在冠状病毒内部，实际上是遗传信息，不是DNA，而是存储在病毒内的遗传信息。你说，好吧，所以它也叫RNA病毒。从多样性的意义上来说，病毒实际上非常复杂。而这个病毒有一个所谓的单链，它是相反的带子，它的强度是一样的，是单链RNA病毒。所以，是的，你有一个刺突蛋白。这是一种苹果蛋白质。另外，如果你有一层层的膜限制，并且在该过程的表面上到处都有膜蛋白。谢谢。

Well, coronavirus is a okay, of course, covet was the hidden in the world in the last few years. But the virus that causing the disease was sort of has been around for ages. The coronavirus has been there are are many subtype of coronavirus, okay? If you look at the sequence, um, alignment of if you compare the sequence of the coronavirus, one of the experts in hong kong is actually a professor. You want your go on the uh for. Okay, professor you at the hong kong, you and then he he many of the centers sequence by him. Um, and and then uh if you look at the sequences of the corner rivals, they can be classified into 4 types of 4 groups. They need offer beta, gamma, and delta.
好吧，冠状病毒是好的，当然，过去几年里，人们的贪婪是隐藏在世界里的。但引起这种疾病的病毒已经存在很多年了。冠状病毒有很多亚型，好吗？如果你看一下序列，嗯，如果你比较一下冠状病毒的序列，香港的一位专家实际上是一位教授。你想要继续呃。好的，你在香港教授，你和他，他的许多中心序列都是由他完成的。嗯，然后呃，如果你看一下角球对手的顺序，他们可以分为 4 类 4 组。他们需要提供 beta、gamma 和 delta。

Okay. For all color runners, we know so far that can invent human that can infect us. They all belongs to either the office of rome. Yes. Or the dangers of growth. That's use the revision of hohcov is a human coral hours. So that after many ministry, um, these string layer can arrive as 2 to 90 has been around for some time before covered and before some probably i'm not sure.
好的。对于所有彩色跑步者来说，到目前为止我们知道可以发明可以感染我们的人类。他们都属于罗马办事处。是的。或者成长的危险。这是使用 hohcov 的修订版是人类珊瑚时间。因此，经过多次的努力，嗯，这些字符串层可以到达，因为 2 到 90 已经存在了一段时间，然后才被覆盖，在一些可能我不确定之前。

You know, there was actually a yeah, so and and they were only, you know, um, has been around that we in fact human, but in but it did not cause a lot of problems just common cold. And the things that the that would actually cost the first. Um, and then it will epidemic that that was actually happened in 2003. Were you bought that1 year or 2 years, something like that? 2 years old? Okay. Um. I think this was actually also the the i'm not sure if you've heard about sars. So guys, this is the first version of the corner. I was that caused a big problem. Um, and a lot of people in the, I think, uh in mainland china and especially in hong kong, a lot of people die at that time. And and and it hit hard, at least in this region of the world that and this is actually called the sars sars actually corresponding to a shock point for sofia. Acute respirator is in on chalk on stops.
你知道，实际上有一个，所以，他们只是，你知道，嗯，一直存在于我们实际上的人类周围，但它并没有引起很多问题，只是普通感冒。而那些实际上首先要花费的东西。嗯，然后就会流行起来，这实际上发生在 2003 年。你买的是 1 年还是 2 年之类的？ 2岁？好的。嗯。我想这实际上也是我不确定你是否听说过非典。伙计们，这是这个角落的第一个版本。我就是那个造成了大问题。嗯,我想,呃在中国大陆,特别是在香港,很多人在那段时间死了。至少在世界这个地区，这受到了严重打击，这实际上被称为“非典”，实际上对应于索菲亚的冲击点。急性呼吸器在停止时用粉笔记录。

Ok so this actually the sars virus belongs to the beta of growth of the coronavirus. But if you i'm not sure if you know this, it's a nurse.
好吧，这实际上是 SARS 病毒属于冠状病毒的 Beta 版。但如果你不确定你是否知道这一点，那是一名护士。

Okay, and okay, I think after I think it died down much quicker than cold in the past 2003, may be affecting this region of the world for maximum 1 year or maybe less than a year. And like over again, has been around for uh uh for much longer time and they die down.
好吧，好吧，我想，在我认为它比 2003 年的寒冷消退得快得多之后，可能会影响世界这个地区最长一年或可能不到一年。又像一遍，已经存在了更长的时间，然后它们就消失了。

Okay, people thought, at least I thought I was actually working on uh um on on on the on the research, on the south protein. And then the well, um, we thought, well, you never come back, okay, that is okay, we will be safe, but actually it's not okay in the around 2012, okay? Probably you were like 10 years teenagers, okay, oh. And then it hit again to build them, but in this time, not in this region, okay? In the middle east. So that's why it's called the middle east, west greater, et cetera. Okay. And of course, a lot of people die. And in fact, we did not hong kong. I'm not sure in china. We actually the the disease actually sort of localized in that region, although it it kills uh uh quite quite quite a number of people. And then, uh, you know, lighten, you know, sometimes, uh, again, when it died down, we thought, well, maybe we are safe, but well, not quite probably the rest is history.
好吧，人们认为，至少我认为我实际上是在研究南方蛋白质。然后，嗯，我们想，好吧，你再也不会回来了，好吧，没关系，我们会安全的，但实际上在 2012 年左右就不行了，好吗？也许你就像 10 岁的青少年，好吧，哦。然后它再次来建造它们，但这次，不是在这个地区，好吗？在中东。这就是为什么它被称为中东、大西部等等。好的。当然，很多人都死了。而事实上，我们没有香港。我不确定在中国。事实上，这种疾病实际上只发生在该地区，尽管它杀死了相当多的人。然后，呃，你知道，减轻，你知道，有时，呃，再次，当它平息下来时，我们想，好吧，也许我们是安全的，但是好吧，不太可能剩下的就是历史了。

And then the in 2000, nineteen and 20 years, right? We have this hope. Probably everybody knows you were much grown up now, right? So and in this time, this is actually caused by and actually this is very simple. Okay? Now people call it the sars hole sars corner as version two. Okay. Uh, mark two. And and this one is even an upgraded one. And probably, you know, it. In fact, I don't know. Millions is not millions of people, not billions of people over the world. And it costs a lot of uh uh economic problem over in europe, in mainland china, in america, and society are sort of suffer. And for gamma and and delta where we they do not infect humans, but they infect like birds. And that's right. Now, if if now is a theory that the coronavirus has a you know, like I have some mutations in this animal like that, and then they they all this recombination and things like that. And they come back to to to the effect of humans.
然后是 2000 年、十九年和二十年，对吗？我们有这个希望。也许每个人都知道你现在已经长大了，对吧？那么这个时候呢，其实是由这个原因造成的，其实这个很简单。好的？现在人们把它称为SARS洞SARS角作为第二版。好的。呃，标记二。而且这还是升级版。也许，你知道，它。事实上，我不知道。数百万人不是全世界的数百万人，也不是数十亿人。在欧洲、中国大陆、美国，这造成了很多呃呃经济问题，社会也受到了一些影响。对于我们这里的伽玛和三角洲，它们不会感染人类，但它们会像鸟类一样感染。没错。现在，如果现在有一种理论认为冠状病毒有一个你知道的，就像我在这种动物身上有一些突变一样，然后它们就会发生重组之类的事情。他们又回到了人类的影响。

Okay, so, yeah. So before we talk about therapies, you know, what what are the way, you know, what what are the strategy to to develop some drugs for the covet, for the covet 19? I have to explain to you why this virus us is so nasty. Okay, so you can say that are like four stage from zero stage. Zero stage is uh, well, no infection. Okay, uh, or no symptoms. Okay, no, no, it's basically no, no infection. Um, uh, and and then maybe in the stage one, you've got some early infections. And then okay, and then you don't know what stage zero.
好吧，所以，是的。因此，在我们谈论疗法之前，您知道，为贪婪、为贪婪 19 开发一些药物的方法是什么，您知道，策略是什么？我必须向你解释为什么我们的病毒如此令人讨厌。好吧，你可以说这就像从零阶段开始的四个阶段。零阶段是呃，好吧，没有感染。好吧，呃，或者没有症状。好吧，不不，基本上没有，没有感染。嗯，呃，然后也许在第一阶段，你会出现一些早期感染。然后好吧，然后你就不知道什么是零阶段了。

Anyway, if you don't have any symptoms, right? The first 1 or 2 day, you don't have any symptoms. It could be have no infections or you are, in fact, but you did not know. And then in the stage one is uh classified as the early infection, where the you got, you know, the the virus will infect your lung cells, and then other infections, the the viral virus to replicate inside most likely alone. Okay. But um, and they they they would infect more cells. And then the the replication would be would actually, the infection will cause some of your cells to die. Okay? And then after cell death, okay, now you're getting a little bit more serious. Okay? Now, when enough of your lung cell get infected is like a cascade is like going downhill, and then probably you'll end up to a stage number two where because of the the cell, the infection did not kill you directly. Unfortunately, unfortunately, okay, it is the the infection that caused the explanations and the information. And and it cost cost, information inclinations, you know, in the long cell, which can be catalyzed.
无论如何，如果你没有任何症状，对吧？最初 1 或 2 天，您没有任何症状。它可能没有感染，或者事实上您是感染的，但您不知道。然后在第一阶段被归类为早期感染，你知道，病毒会感染你的肺细胞，然后是其他感染，病毒很可能会在内部复制。好的。但是嗯，他们会感染更多的细胞。然后复制实际上会是，感染会导致你的一些细胞死亡。好的？然后在细胞死亡之后，好吧，现在你的情况变得更加严重了。好的？现在，当足够多的肺细胞被感染时，就像级联一样，就像走下坡路一样，然后你可能最终会进入第二阶段，由于细胞的原因，感染不会直接杀死你。不幸的是，不幸的是，好吧，是感染导致了解释和信息。而且它会花费成本、信息倾向，你知道，在长单元中，这是可以催化的。

Now you get into second stage. And probably in between uh stage one or stage two, you. Okay, um, and and you have some symptoms like having a fever. Okay. The temperature and your body temperature go go high. You have a drive code, okay? Okay, quite a lot. Okay, are you? Okay? Sometime, but but it depends on who, okay, I heard I had friends, okay? They do they do have very slightly different symptoms. Okay, um uh if you had it, but but if you some most of, okay, if you got fascination or if you're lucky, most of the people don't go beyond that. But if you are lucky, some of the people would get a severe lung inflammation. Okay? That uh, that would basically is like a cascade going downhill. And probably at this day, you start to have some symptoms of a short list of breath, because some of the lung cells got implemented, and then uh, it actually reduce the functions of your lung, okay? But of course, for younger people is easier, okay? Because uh, you guys probably have a better lung function for all the people. Their lung is already known as good as you know, younger people, then they may suffer more severe uh symptoms.
现在你进入第二阶段。可能在呃第一阶段或第二阶段之间，你。好吧，嗯，你有一些症状，比如发烧。好的。温度和你的体温都会升高。你有驱动器代码，好吗？好吧，相当多。好吧，你是吗？好的？有时，但这取决于谁，好吧，我听说我有朋友，好吗？他们的症状确实略有不同。好吧，嗯，如果你有的话，但是如果你有大部分，好吧，如果你着迷或者你很幸运，大多数人都不会超越这一点。但如果幸运的话，有些人会患上严重的肺部炎症。好的？呃，这基本上就像瀑布下坡一样。可能在这一天，你开始出现一些呼吸短促的症状，因为一些肺细胞被执行了，然后呃，它实际上降低了你的肺功能，好吗？但当然，对于年轻人来说更容易，好吗？因为呃，对于所有人来说，你们的肺功能可能都更好。他们的肺部已经被认为和年轻人一样好，那么他们可能会遭受更严重的呃症状。

And and and if you really, really are lucky, if the patients got the disease, then we can go to the stage three, where the internet where the information of the long go out of hand. Okay, and then the symptoms also severe that you can get a so called acute respiratory distress syndrome. Okay, basically you you you your none cannot function normally and also system makes systematic, systemic information response. And and basically the the the it's also indeed is not the virus direction that the infection directed qu it is that in the nature is for the q okay, that that you can see that this that because the the body uh human body is trying to react to the foreign pathogen of the virus and then and then get a lot of this information in response.
如果你真的真的很幸运，如果病人得了这种病，那么我们就可以进入第三阶段，在这个阶段，互联网上的信息将失控。好吧，症状也很严重，你可能会患上所谓的急性呼吸窘迫综合症。好吧，基本上你你你你都不能正常运作，系统也会做出系统的、系统的信息反应。基本上，这也确实不是感染所指向的病毒方向，它本质上是为了 q 好吧，你可以看到，这是因为身体呃人体正在试图做出反应病毒的外来病原体，然后得到很多这样的信息作为反应。

And then finally, if you are lucky, carry a rest and you can go to peace, okay, red dress in peace. Okay, someone we we cover of the space three depends. I mean, and then it depends on. And now we talk about after covet oka lot of people. This is actually some kind of long cover, some sort of opposed cover syndromes. Okay? Um, uh, my my wife told me that after cover she lost, you know, some, you know, he cannot remember things, okay? Maybe i'm not sure is this completely true. Uh, I sometimes cannot remember a lot of things. So uh, but but essentially in the returns of research, there are some report talking about some or some of the long term symptoms, okay, a side effect after you got a covert. So but okay, like a fatigue, I don't know, ii will always do this, but i'm not sure you said ii got coffee once, I think maybe too, I don't know, okay. Um, paying whatever. Okay? So depending on which stage you are in, okay, you can talk about different measures of treatment or drugs, ok or medications to help the patients.
最后，如果你幸运的话，休息一下，你就可以去平静了，好吧，平静地穿红衣服。好吧，我们要报道的第三个空间取决于谁。我的意思是，然后这取决于。现在我们谈论很多人的觊觎之后。这实际上是某种长掩护、某种对立掩护综合症。好的？嗯，呃，我的妻子告诉我，在掩护之后，她失去了，你知道，有些，你知道，他不记得事情了，好吗？也许我不确定这是否完全正确。呃，我有时候记不住很多事情。所以呃，但本质上，在研究的回报中，有一些报告谈论了一些或一些长期症状，好吧，是隐秘后的副作用。所以但是好吧，就像疲劳一样，我不知道，我会一直这样做，但我不确定你说我喝过一次咖啡，我想也许也是，我不知道，好吧。嗯，随便付钱。好的？因此，根据您所处的阶段，好吧，您可以谈论不同的治疗措施或药物，好吧或药物来帮助患者。

Okay, so if you are, in my opinion, the past is still to get the western nation at stage zero.
好吧，如果你是，在我看来，过去仍然是让西方国家处于零阶段。

Okay, okay, maybe uh so before you got got anything and then there's actually a lot of people talking about, although there's a lot of media talk about uh vaccine phobia, okay, uh uh hesitation in in the vaccine, but the data are are actually quite convincing that getting some sort of resignation were actually it did not actually prevent you from getting covered, but it increased your chance of survival.
好吧，好吧，也许呃，所以在你得到任何东西之前，然后实际上有很多人在谈论，虽然有很多媒体谈论呃疫苗恐惧症，好吧，呃呃在疫苗方面犹豫不决，但数据是实际上，相当令人信服的是，获得某种辞职实际上并没有真正阻止您获得保险，但它增加了您的生存机会。

Okay? You can still get over that. Okay? Or i'm not sure, I guess you you must have some experience, right? I got over it after three dose, okay? But I didn't die, right? So it helps um, ok so that before you get a copy may maybe in the very early state, you can still maybe it still can beneficial before. And then, um, and then throughout the um, you know, you can give up some inhibitors that will be the focus on today's um, lecture, on some drugs that can inhibit the viral infections. Okay? But I would say a lot of all these drugs would be best take it in the stage one where the virus infection are actually is not as uh serious, because once your infections start to go around and start to get something to make a response, then it it it could be a little bit too late. A little bit late. It's not too late, but this is a little late.
好的？你仍然可以克服这个问题。好的？或者我不确定，我猜你一定有一些经验，对吧？我服了三剂就痊愈了，好吗？但我并没有死，对吧？所以它会有所帮助，嗯，好吧，这样在您获得副本之前可能处于非常早期的状态，您仍然可以也许它仍然可以在之前受益。然后，嗯，然后在整个嗯，你知道，你可以放弃一些抑制剂，这将是今天嗯讲座的重点，关于一些可以抑制病毒感染的药物。好的？但我想说，所有这些药物中的很多最好在病毒感染实际上没有那么严重的第一阶段服用，因为一旦你的感染开始四处传播并开始得到一些东西来做出反应，那么它可能有点太晚了。有点晚了。还不算太晚，但这有点晚了。

And uh and I guess most of the people who got a coffin would take some fee for using agent Like and a door, okay? That would uh uh reduce the symptoms. Okay? I think when I got a coffee, I did that, okay? And as a state, uh, you know, rest for one weekend and people recovered. And so I guess most of the people will recover, you know, at somewhere. Yeah, but if you if the internationally response get more serious, probably you need to uh get some drugs to suppress your immune response. Yeah, this is they are called, you know, all the letters that, you know, uh, because why we fashion on its own does not kill you directly.
呃，我想大多数得到棺材的人都会收取一些使用代理费用和门的费用，好吗？那会呃呃减轻症状。好的？我想当我喝咖啡时我就这么做了，好吗？作为一个州，呃，你知道，休息一个周末，人们就会康复。所以我想大多数人都会在某个地方康复。是的，但是如果你的国际反应变得更加严重，你可能需要呃服用一些药物来抑制你的免疫反应。是的，这就是它们的名字，你知道，所有的字母，你知道，呃，因为我们自己的时尚并不会直接杀死你。

Okay, if you can suppress the the immune response that caused the the the inclinations, okay, at least it could, you know, save your life and wait for the body to get rid of the virus or eventually. But but sometimes it is a serious. You may need to have some sort of oxygen supplementation. You wear some mask to to, you need to uh some supplement with oxygen. You need to bring in oxygen to help, because the lung cells are not as good as it should be. That would actually, we cannot uh uh uh take in enough oxygen gas. And even for the very severe case, where you may need to have a mechanical um, machine to help you to breathe. Um, so today, probably, i'm going to mainly focus on this part of the antivirus, on the drugs that can inhibit viral the corner rival replication. So before we can do this, I hope I can give a very quick overview on the replication cycle of coronavirus and with the with with the focus on what are the steps that we can intervene uh, to to uh make us intermittent?
好吧，如果你能抑制引起这种倾向的免疫反应，好吧，至少它可以，你知道，拯救你的生命并等待身体摆脱病毒或最终。但有时却很严重。您可能需要补充某种氧气。你戴个口罩吧，你需要呃补充一些氧气。你需要引入氧气来帮助，因为肺细胞没有达到应有的水平。那实际上，我们无法呃呃呃吸入足够的氧气。即使在非常严重的情况下，您可能需要机械嗯机器来帮助您呼吸。嗯，所以今天，可能我会主要关注抗病毒的这一部分，关于能够抑制病毒角对手复制的药物。因此，在我们这样做之前，我希望我能快速概述一下冠状病毒的复制周期，重点是我们可以采取哪些干预措施，让我们间歇性地进行？

So, of course, the first step of our impression would be the virus has to bite to a cell surface receptors. Okay? One of the one of the sensor is called ace two. Another cold receptor is called tmrprss two. Um, it is, uh, and then, uh, if you and the viral has to bind on the surface protein onto the lung cell, and then, uh, and then to get entered into yourself. So there are ways what there are research going on to talk about. How about we can inhibit the interactions of the virus to the lung cells. So, and then after the cell get inside to the cells, the rna will get out the rna within the the genome of the of the uh current arrivals we get out. And rna is they think it's a message rna can be used to direct hijack the um protein synthesis, the machinery within the south, where the the vitamin dna would direct the synthesis of viral proteins.
所以，当然，我们印象的第一步是病毒必须咬住细胞表面受体。好的？其中的一号传感器称为王牌二号。另一种冷受体称为 tmrprss 2。嗯，是的，呃，然后，呃，如果你和病毒必须在肺细胞的表面蛋白上结合，然后，呃，然后进入你自己。因此，有一些研究正在讨论的方法。我们能否抑制病毒与肺细胞的相互作用？因此，当细胞进入细胞内部后，RNA 就会从我们取出的当前到达者的基因组中取出 RNA。他们认为rna是一个信息，rna可以用来指导蛋白质合成，这是南方的机器，维生素dna将指导病毒蛋白质的合成。

And i'm going to explain a little bit detail in the next slide that the viral protein I expressed instead of individual proteins, they express it as the so called poly proteins.
我将在下一张幻灯片中解释一些细节，即我表达的病毒蛋白而不是单个蛋白，它们将其表达为所谓的多蛋白。

Okay? And then you need to chop the poly protein into individual proteins in order for the for the for the viral routines that so and then maybe one way, which is the focus of today's lecture is uh, on finding drugs to interpret this process.
好的？然后你需要将多聚蛋白切成单独的蛋白质，以便用于病毒的常规，然后也许有一种方法，这就是今天讲座的重点，呃，寻找药物来解释这个过程。

Okay? If the, yeah, if the viral protein cannot be processed properly to be functional, okok the virus, the virus cannot reference. And then, again, another thing is, uh, the another step that um, people can develop drop. It is uh to uh, and then, of course, the viral protein can also produce an enzyme called rna polymerase. Okay? Is the rna dependent rna polymerase? Basically, it it tried to photocopy for number one, copy the rna into more copies. Okay? So eventually, and this, uh, this is uh, um, um, rna would make more primary protein. And then and then at the end of uh of life cycle, all these virus, viral protein would then packaged into a whole virus. Okay? That could be another step of interventions. And then the the virus will release and then to um, inhibit other cells, corporate lung cells, be about. And today, i'm going to look at uh, mainly focus on on this guy, on the viral programs. It's a complicated slide. So here, this is the genome of the virus of the virus is contained 29,000 base pair are are a different type.
好的？如果，是的，如果病毒蛋白不能被正确加工以发挥功能，那么病毒就无法引用。然后，再一次，另一件事是，嗯，人们可以发展的另一个步骤下降。就是呃对呃，然后当然病毒蛋白也能产生一种叫做RNA聚合酶的酶。好的？ RNA 依赖性 RNA 聚合酶吗？基本上，它首先尝试复印，将 RNA 复制成更多副本。好的？所以最终，这个，呃，这是呃，嗯，嗯，RNA 会产生更多的初级蛋白质。然后然后在生命周期结束时，所有这些病毒、病毒蛋白将被包装成一个完整的病毒。好的？这可能是干预措施的又一步。然后病毒会释放出来，然后抑制其他细胞，比如肺细胞。今天，我要看看呃，主要关注这个人，病毒式传播的节目。这是一张复杂的幻灯片。所以在这里，这是病毒的基因组，该病毒包含29,000个碱基对，都是不同的类型。

And then for most of the protein, except this is uh these protein service protein and the protein uh nuclear protein that responsible for making a mature virus. Most of the proteins that are essential for the rapid dna for the rna for the viral replication, are expressed as a so called tonic protein. Okay? Party broke a very, very long, very long political touching. And then within the polypeptide, we call it polypropylene. So because like a lot of human protein, we express uh intensely, it's a single protein. And we express the mild globe is also another single protein expressed one by one. But for for for viruses are very often. They will express the protein link up together as a very long polypeptide chain, the very long proteins.
然后对于大多数蛋白质，除了这些蛋白质服务蛋白质和负责制造成熟病毒的蛋白质呃核蛋白质。大多数对于病毒复制的RNA快速DNA所必需的蛋白质都被表达为所谓的补品蛋白质。好的？党断了很长很长的政治感人。然后在多肽中，我们将其称为聚丙烯。因为像许多人类蛋白质一样，我们强烈表达，它是单一蛋白质。而我们表达的温和球体也是一一表达的另一种单一蛋白。但病毒却很常见。它们将表达连接在一起的蛋白质，形成一条很长的多肽链，即很长的蛋白质。

And then, so for example, this poly protein contain, oh, let me come 1232, 16. Okay, 16, 16, nsb of stanford, non structural protein. Okay. Ah, this distinguished from the structural protein, semn structure structural remains. These are the protein that finally, okay, will be matched. It would be incorporated into the mature virus. So these are these non structural proteins of section of them link up together to form a so called a single polypeptide chain with 16 protein. So you can imagine you need enzymes which approach is to chop them into individual protein for those protein to be function.
然后，例如，这个多聚蛋白含有，哦，让我来1232, 16。好的，16, 16，斯坦福大学的nsb，非结构蛋白。好的。啊，这个区别于结构蛋白，semn结构仍然是结构。这些是最终会匹配的蛋白质。它将被整合到成熟的病毒中。所以这些非结构性蛋白质的一部分连接在一起，形成所谓的由16个蛋白质组成的单一多肽链。因此，您可以想象您需要酶，其方法是将它们切成单独的蛋白质，以使这些蛋白质发挥作用。

Okay, within the voluntary notes, there are actually two projects. One protein is called plpa pine, like a pines, like proteins of plp which is on his own, is uh, one of the uh non structural protein located at number three decisions. Another protein is another protein is called the main proteins of dependent on some literature. Some people call it vc light proteins. But in this lecture, I prefer to use the main proteins. Is easier to remember is the the main protests are the most important protests, okay? Uh, uh which is that you're located at number five positions of this foreign peptide chain. And the the pine light protein protest prp is responsible for cutting here, here, and here. So if you only have plp in your that you'll be able to ask the bible, the virus can only be able to cut the first three for uh, for the main protests. They cut all the rest ok kind of disposition. And then we'll be responsible for releasing uh, sp 456 to 16.
好吧，在自愿笔记中，实际上有两个项目。一种蛋白质被称为 plpa pine，就像松树一样，就像 plp 的蛋白质一样，它是独立的，是呃，呃非结构蛋白之一，位于第三个决定。另一种蛋白质被称为依赖于一些文献的主要蛋白质。有人称其为vc轻蛋白。但在本次讲座中，我更喜欢使用主要蛋白质。更容易记住的是主要抗议是最重要的抗议，好吗？呃，呃，也就是说你位于这个外源肽链的第五位。而松光蛋白抗议prp负责切割此处、此处和此处。因此，如果你只有 plp 可以询问圣经，那么病毒只能削减前三个，呃，主要的抗议活动。他们把剩下的一切都剪掉了。然后我们将负责发布呃，sp 456 到 16。

Of course, the uh, all these proteins have their own functions. Here. I'd like to introduce uh, one um, protein, which is, actually, I mentioned already, this is the rna polymerase that are responsible for replicating the rna into many, more copies so that this rna can be incorporated into viruses. Okay? That can be, you know, uh, uh, uh, use it to when they mature, they can use it to uh, he found ourselves.
当然，呃，所有这些蛋白质都有自己的功能。这里。我想介绍一下呃,一个呃,蛋白质,其实就是,我已经提到过,这是一种RNA聚合酶,它负责把RNA复制成很多很多的拷贝,这样这个RNA就可以掺入到病毒中。好的？那可以是，你知道，呃，呃，呃，用它来当他们成熟时，他们可以用它来呃，他找到我们自己。

So again, okay, um, among these, um, uh, 16 non structural protein, um, nsp 12, which is the rna polymerase, and the nsp five, the main proteins are from targets. I'm not sure if you still, uh, remember, in the very first year, uh, maybe 2020, maybe late 19. That was a that's a drug call. Um, grand festival. I don't know the chinese name.
那么，好吧，嗯，其中，嗯，嗯，16 个非结构蛋白，嗯，nsp 12，这是 rna 聚合酶，还有 nsp 5，主要的蛋白质来自靶点。我不确定你是否还记得，呃，在第一年，呃，也许是 2020 年，也许是 19 岁末。那是一个毒品电话。嗯，盛大的节日。我不知道中文名字。

Okay? Uh, this is essentially uh, one of from the uh uh, uh, to lead science. This is actually one of the first drop that, uh, it was used to treat, covet. Okay? Um, and this is actually, um, inhibitor for this rna polymerase. So obviously, if you inhibit the rna polymerase, the rna can no longer copies of rna so which means they cannot be replicated. And now, the and other enzymes that are and an important drug target is the main projects that is far. And today, i'm going to mainly focus on this answer. In fact, this is the another uh, inhibitor called the and the math refer. And and this is actually uh, got it out to market uh, by the company. Again. I so I shall be a problem. Okay, for for corporate. So, yeah. Okay. As I said, okay, in today's lecture, I will be focused on. This ends up with the main proteins as a drug target.
好的？呃，这本质上是呃，呃呃，呃，引领科学之一。这实际上是第一滴，呃，它被用来治疗、觊觎。好的？嗯，这实际上是，嗯，RNA 聚合酶的抑制剂。显然，如果抑制 RNA 聚合酶，RNA 就无法再复制 RNA，这意味着它们无法复制。现在，酶和其他重要的药物靶点是目前的主要项目。今天，我将主要关注这个答案。事实上，这是另一个呃，抑制剂，称为数学参考。这实际上是呃，由公司把它推向市场的。再次。我这样我就会有问题。好吧，对于企业来说。所以，是的。好的。正如我所说，好吧，在今天的讲座中，我将重点讨论。最终以主要蛋白质作为药物靶点。

So obviously, why why why this is so good? Okay. In fact, this is the one that is, in my opinion, that has been go on to the market. And it is useful. Um. Okay, first of all, main protein is is required for wire representation, as I explained in the last slide, viral proteins, a lot of other non structural protein are expressed in the pot protein. You need the main protein to chocolate. Okay? It's a functional protein before it can be uh uh, the viral the riders can can replicate.
很明显，为什么这这么好？好的。事实上，在我看来，这就是已经投放市场的产品。而且它很有用。嗯。好的，首先，主要蛋白质是线表示所必需的，正如我在上一张幻灯片中解释的那样，病毒蛋白和许多其他非结构蛋白都在罐蛋白中表达。您需要巧克力的主要蛋白质。好的？它是一种功能性蛋白质，然后才能成为骑手可以复制的病毒。

Second of all, the substrate specificity of the proteins is actually conserved among all kind of rivals. Okay. Um, i'm going to show you some data. I work on this uh10 years ago. I did not work on that anymore. I thought the whole sars did not come back. So you know, ii stopped doing that more than 10 years ago. But ii can show you some data uh of our data. Um the the the substrate specificity essentially very concerned concerns, which means that uh um, I can bet the drug developed for cope with 19 should be should okay, should be equally applicable to the first version of the officer. They they they basically they are almost excited like that. Bad size, almost. You talk about 99% of sequence analysis between the first version of sars. Congress uh protest at the covid two. Yeah. Um, so which means that you can who then you can actually develop a inhibitor that can inhibit, in case, hopefully, you know, hopefully will not come back, but in case it come back again.
其次，蛋白质的底物特异性实际上在所有类型的竞争对手中都是保守的。好的。嗯，我要给你看一些数据。我十年前就在研究这个。我不再做这件事了。我以为整个SARS都没有回来。所以你知道，我十多年前就不再这样做了。但我可以向您展示我们数据中的一些数据。嗯，底物特异性本质上是非常令人担忧的问题，这意味着嗯嗯，我可以打赌，为应对19而开发的药物应该应该没问题，应该同样适用于官员的第一个版本。他们基本上他们几乎是那样兴奋。尺寸不好，差不多。你谈到了第一版SARS之间99%的序列分析。国会呃抗议新冠病毒二号。是的。嗯，这意味着你可以开发出一种抑制剂，可以抑制万一，希望，你知道，希望不会回来，但万一它再次回来。

Okay, the corner of us, then the existing inhibitor could still be a very good signing. to develop some new order to come back those new intentions. So ferry themselves. Um, um, unlike for example, you know, probably you heard about the story where the vessel becomes useless, okay? After a few generations. Okay, this is essential because the the surface protein, one of them is that the the spike protein, they have a lot of mutations like all this omicron on this delta variant, wherever they have a lot of musician. That would because this is a protein where the antibody medicine, right, that anybody had to interact. And they have a lot of mutations.
好吧，我们的角，那么现有的抑制剂仍然可能是一个非常好的签约。制定一些新的秩序来恢复这些新的意图。于是自己摆渡。嗯，嗯，不像例如，你知道，你可能听说过容器变得无用的故事，好吗？几代之后。好吧，这很重要，因为表面蛋白，其中之一是刺突蛋白，它们有很多突变，就像这个 delta 变体上的所有 omicron，无论哪里有很多音乐家。那是因为这是一种蛋白质，其中抗体药物，对，任何人都必须相互作用。而且它们有很多突变。

So that's why it's difficult. But for the main protein is the the the mutations across different strain belong that many. They are very difficult. And there's actually a reason why it has to be conserved, because the clip is secret of as before to as before 16. You see, in order for it to function, you need to cut the protein correctly. So so you can imagine, if you mutate, the protein is too much. It will become useless because the cliff is secret. Uh, among this, you know, about this nsp 4 and 15, they actually went to concern. So it's actually uh, will be difficult for the virus to develop the system. I did not say impossible, okay? Never say never. But but it will be more difficult to develop a system uh, without affecting its own processing of particles.
所以这就是困难的原因。但对于主要蛋白质来说，不同菌株之间的突变属于很多。他们非常困难。实际上，它必须被保存是有原因的，因为该剪辑和以前一样是秘密的 16。你看，为了让它发挥作用，你需要正确地切割蛋白质。所以你可以想象，如果你变异了，蛋白质就太多了。它会变得毫无用处，因为悬崖是秘密的。呃,这其中,你知道,关于这个nsp 4和15,他们其实是去关注的。所以实际上呃,病毒开发这个系统会比较困难。.我没有说不可能好吗？永不说永不。但是但是要开发一个系统呃不影响自己处理粒子的话会比较困难。

And finally, the 4th point is, there are actually not no, no proteins that would have a similar substrate specificity of the main protest, because it's a protest, right? You if if you um if this protein is cut your own human protein randomly, right? Then you all then you end up with a lot of side effects, right? Uh, but luckily, it's not okay. It's uh, because i'm going to tell you that the sequence specificity of this enzyme are very different, because of viral origin is very different from uh, from human approaches. So there are actually no, no protest that we share is the same substance of simplicity, which means that less side effect, lower chance to develop a side effect. So, um, then I get a little bit in order to understand how to we know, what are the strategy to develop, drop for this main proteins? Uh, bear with me. Okay? I'd like to have a very quick introductions of how a proteins of outer enzyme was. We need to understand the mechanism of how the enzyme works.
最后，第四点是，实际上没有、没有蛋白质具有与主要抗议类似的底物特异性，因为它是抗议，对吧？你如果如果这个蛋白质是你自己的人类蛋白质随机切割的，对吧？那么你们最终会产生很多副作用，对吗？呃，不过幸运的是，没问题。呃，因为我要告诉你，这种酶的序列特异性非常不同，因为病毒起源与呃，人类方法非常不同。所以实际上没有，没有抗议，我们分享的是相同的简单实质，这意味着副作用更少，产生副作用的机会更低。所以，嗯，然后我想了解一点，以便了解我们如何知道，开发这种主要蛋白质的策略是什么？呃，请耐心听我说。好的？我想快速介绍一下外部酶的蛋白质是如何的。我们需要了解酶的工作机制。

So, um, I joined myself. It's not very beautiful, but you got the idea. So this is the main proteins. You've gotta exercise somewhere here. The most important of amino acids that are responsible for the catalysis that is a special 16residue, 16. Who remember that? Okay, at position number145. Okay, this is very important residues. If you kill this residue, if you mutate this residue to, for example, all these the xi become inactive. Okay, so this is the active site residents. So and then assuming you have aa substrate, right? Is the polypeptide chain, what substrate is a protein? So it's a polypeptide chain. So I tried to draw the polypeptide somewhere here. Okay? And of course, it would recognize the binding site would bind to the active site. And then the cysteine residue, which is the axis of residue aspect, one of the peptide bonds. The bond to be clear, um, typically in the literature we call it the sisal peptide bond is the peptide bond to be cut over the system, right? To be to be cut over that bond is called the system.
所以，嗯，我自己也加入了。它不是很漂亮，但你明白了。所以这是主要的蛋白质。你必须在这里锻炼身体。负责催化作用的最重要的氨基酸是一种特殊的 16 个残基，16。谁还记得这个？好的，在 145 号位置。好的，这是非常重要的残留物。如果你杀死这个残基，如果你突变这个残基，例如，所有这些 xi 都会变得不活跃。好的，这就是活跃站点的居民。那么假设你有一个底物，对吧？是多肽链，什么底物是蛋白质？所以它是一条多肽链。所以我试图在这里的某个地方画出多肽。好的？当然，它会识别结合位点将与活性位点结合。然后是半胱氨酸残基，它是残基方面的轴，肽键之一。要明确的键，嗯，通常在文献中我们称之为剑麻肽键，是要在系统上切割的肽键，对吗？被切断的这种联系被称为系统。

And and then the um, the mechanism would be. And after the bond is broken, that would be an important intermediate where the system have seen as the interesting is a as an ethical style world. The ethic would actually uh serve as uh would attack this bond that would form a covalent bond with one of the companies.
然后嗯，机制就是。在债券被打破之后，这将是一个重要的中间体，系统将其视为有趣的道德风格世界。实际上，道德规范会攻击这种与其中一家公司形成共价键的债券。

And then and then the rest of the polypeptide chain would go is because cut off again. And in the second stage of the protease reaction, a water will come in and complete. The hypothesis is the form will be broken. And then the the enzyme going back to the initial stage. Yeah. I'll i'll need to explain to you a little bit of people when they talk talk about drug development of this protest, we need to need to uh uh like count the the the rich uh the residue.
然后剩下的多肽链就会消失，因为再次被切断。而在蛋白酶反应的第二阶段，会有水进入并完成。假设形式将会被打破。然后酶回到初始阶段。是的。当人们谈论这次抗议的药物开发时，我需要向你们解释一下，我们需要嗯嗯，比如计算富人呃残留物。

So assuming, so assuming this is the systobal, the proteins would cut open at this position. So these are the imminent assets. So the so by conventions, people in the protest field would actually look at this for those on the distance. And typically, for even as a protein, by convention, we read the even asset from the n terminus to the c terms, right? And to c terms. And then this is the sister about the residue to the and then and then, on the other hand, for the for people who get to count the number of residue from the is not long. P one was sent to the the first residue on the antenna size of the of the polypeptide chain and p two followed by p two, p three, and p four. So if this is the system, so this will be p one, p two, p three, p four. And again, to the other side of the system, we call it p one pie. We've got this is probably with the bright side you.
所以假设，假设这是收缩期，蛋白质会在这个位置切开。所以这些是迫在眉睫的资产。所以按照惯例，抗议现场的人们实际上会为远处的人看这个。通常，即使作为蛋白质，按照惯例，我们也会读取从 n 末端到 c 项的偶数资产，对吧？和c条款。然后这就是姐姐讲的残数到了，然后再，另一方面，对于那些得到数残数的人来说，距离并不长。 P一被发送至多肽链天线大小上的第一个残基，p二随后是p二、p三和p四。所以如果这是系统，那么这将是 p 一、p 二、p 三、p 四。再说一次，对于系统的另一边，我们称其为“p one pie”。我们知道这可能是你的光明的一面。

Okay, and and so and then the next lesson would be to try if you try and people. So, and although this is not the um, you know, very beautiful. It's like a shock to me, but okay, but but i'm going to tell you that uh, for a lot of uh, uh, uh, inhibitor they make use of how the enzymes will react with the p one, p two, p four residues, and then take advantage to the in designing the drug.
好的，等等，然后下一课就是尝试，如果你尝试的话。所以，尽管这不是嗯，你知道，非常美丽。这对我来说就像是一个震惊，但是好吧，但是我要告诉你，呃，对于很多呃，呃，呃，抑制剂，他们利用酶如何与 p 一，p 二反应， p 四个残基，然后利用它来设计药物。

Well, so this is a cartoon, okay, scheme make a diagram. This is the three dimensional structure of the peptide or the substrate in complex with the enzymes.
嗯，这是一部漫画，好吧，计划画一个图表。这是肽或底物与酶复合的三维结构。

So this is, of course, okay, this is just uh, uh, you can see that the the the enzymes are represented in the backgrounds. And the substrate are shown in blue, which is shown here. Okay? The system body is somewhere in here, this part time on. This is the system. Remember, system145 is the axis residues, which is which is part which would attack the society of epsilon. So on this side of the, uh, on the end of the size of the system of the system on, you can count on acid as one, s two, as threes, uh, for this case, debating. And as for allah as five axis and so far and so forth, 77. We can see that. And then on this on this side of the of the c terminal side of the system, or you have s one brine, which is located somewhere, you this is the gliding as to uh uh uh the p two. And this is the p three, and this is the p four.
所以，当然，好吧，这只是呃，呃，你可以看到酶在背景中出现。基板显示为蓝色，如下所示。好的？系统主体就在这里的某个地方，这部分时间还在。这就是系统。请记住，system145 是轴残基，它是攻击 epsilon 社会的部分。所以在这一边，呃，在系统的大小的末端上，你可以指望酸为一，二，为三，呃，对于这种情况，争论。至于安拉是五轴等等，77。我们可以看到这一点。然后在系统的 c 终端一侧的这一侧，或者你有一个盐水，它位于某处，你这是滑翔至 uh uh uh p 两个。这是p 3，这是p 4。

Okay? And then you probably see that corresponding to the enzymes. Okay, that will recognize p one, p two, and so forth, and so forth. They are called subside, s one, and s two, s three, and s four. So so for the enzymes, they have this uh, pocket or substrate binding pocket. They are named a column that would actually interact with the p one, for example, that i'm not sure you can see. Maybe you can see it better in this, uh, no three dimensional, uh, you know, animations. Do you see a pocket here? Get a lot of up in which accommodating the s one. So this is the pocket. So the residue on the substrate is named after p one, p two, and so far and so on. And for the pocket on the enzyme, they are called s one. The sub substrate binding site, okay? Subsidies say, 12uh3°of uh gradually exercise on our work. You've got some feedback. So as for again, this is as for prime, the subsidiary type of p one point. And um, this is, uh, I know how careful has two prime. Uh. So all you can sort of, uh, um, you know, draw it systematically, because this is what happened.
好的？然后您可能会看到与酶相对应的内容。好的，这将识别 p 1、p 2 等等。它们被称为“消退”、“一”、“二”、“三”和“四”。对于酶来说，它们也有这个呃，口袋或底物结合口袋。例如，它们被命名为实际上会与 p 交互的列，我不确定您是否能看到。也许你可以在这个，呃，没有三维，呃，你知道的动画中更好地看到它。你看到这里有一个口袋吗？多做一些事情，以适应 s 的情况。所以这就是口袋。因此底物上的残基以p一、p二命名，依此类推。而对于酶上的口袋，它们被称为s一。子底物结合位点，好吗？补贴说，12uh3°的呃逐渐锻炼了我们的工作。您已收到一些反馈。再说一遍，这就是素数，p 一点的附属类型。嗯，这是，呃，我知道有两个素数有多小心。呃。所以你所能做的就是，呃，嗯，你知道，系统地画出来，因为这就是发生的事情。

So I like to and why they interact, because they they either who the formations of atom bond, for example, for the s one topic, they recognize a due to mean residues, because they can form two hydrogen bond that will recognize the amide functional growth of the peel and recipe of the duty ok this is indeed on the bond here.
所以我喜欢为什么它们相互作用，因为它们要么形成原子键，例如，对于第一个主题，它们识别由于平均残基，因为它们可以形成两个氢键，这将识别酰胺官能团果皮的生长和责任的配方好吧，这确实是在这里的债券上。

And for the s two pockets as a hydrophobic, ok, which is actually located somewhere in, i'm not sure it's a serious, which is uh, will interact with the hydrophobic residues of illusion at p two positions and so on.
对于 s 两个口袋作为疏水性，好吧，它实际上位于某处，我不确定它是否严重，呃，会与 p 两个位置处的疏水残基相互作用，依此类推。

So, um, a little of my own own research. Uh, um. I didn't I didn't lie to you. Uh, this is the paper. I published the2010, okay? It was like 14 years ago. And at that time, I was trying to devote a assay, okay, to testing and semantic activities of sars. There was a version one, okay? Coffee did not came in2010. And I worked on the first versions of the softer could be uh, main proteins. And this is something I developed. I expressed a protein, which is, uh, uh, on one hand, got a uh, a cyan for some protein.
所以，嗯，我自己的一些研究。呃，嗯。我没有，我没有骗你。呃，这是纸。我出版了2010年，可以吗？那就像是14年前的事了。那时，我正试图致力于一项分析，好吧，对非典的测试和语义活动。有一个版本，好吗？ 2010年咖啡没有来。我研究了第一个版本的软蛋白，可能是呃，主要的蛋白质。这是我开发的东西。我表达了一种蛋白质，呃，呃，一方面，某些蛋白质是呃，青色的。

And then with the link containing the sequence of uh, of the, uh, the cutting sequence of the main proteins, which come here somewhere, and then followed by a uh, yellow forest approaching yfp so, so, um, the idea is, so this is the fusion protein complaining to forest and protein. One is cyan, one is yellow linked together by the sequence. You know, the peptide seven that are cut by the proteins. So uh, before. So this is a simple, I think if you've done the six two hundred, right, six two thousanduh, a lab, however, you see, this is like ss page. Okay, um, and then the before cutting you, the the protein would be have something like, uh, 50is a killer thousand, then if after you add the enzyme, the the protein will be cut into two half, okay? Of around 30 kilos dollars each. 20something, 32,000age. And the idea is, so, um, the the one we can actually develop this essay is take advantage of the better these protein can give, for essence.
然后是包含呃序列的链接，呃，主要蛋白质的切割序列，它来到这里的某个地方，然后是一个呃，黄色森林接近 yfp 所以，所以，嗯，这个想法是，所以这是向森林和蛋白质抱怨的融合蛋白。一种是青色，一种是黄色，按顺序连接在一起。你知道，被蛋白质切割的肽七。所以呃，之前。所以这很简单，我想如果你已经完成了六两百，对吧，六两千，一个实验室，但是，你看，这就像 ss 页面。好吧，嗯，然后在切割你之前，蛋白质会是这样的，呃，50是一个杀手千，那么如果你添加酶之后，蛋白质将被切成两半，好吗？每份30公斤左右。 20多岁，32000岁。这个想法是，所以，嗯，我们实际上可以开发这篇文章的是利用这些蛋白质可以提供的更好的精华。

Um, for example, um, if we take advantage of a phenomenon called, for instance, resonance energy transfer or cold friend, okay, the idea is this, uh, the science, the cfb the sign for a certain proteins, can be excited by glue. It may be a uh, uh, blue lights are at450, uh, 413, and after some blue light. And then once this science cfp is excited, they can give out science uh uh give us, for essence. And the fluorescence can entire used it to excite the ghetto for some protests. And the yeah, fluorescent protein. It is excited by the site at cfp then he can imitate, for essence, at530 an hour. The idea is this this kind of, uh, you know, resonance transfer from the scion force of protein to the yellow force of protein only occur, only occur when the true protein are in proximity to each other. So assuming this is the cyan protein, this is the yellow fluorescent protein, this kind of, you know, excitation across this protein, because the fact, for essence, uh, resonance energy transfer only occur when this protein is linked up together.
嗯，例如，嗯，如果我们利用一种称为共振能量转移或冷朋友的现象，好吧，这个想法是这样的，呃，科学，cfb 是某种蛋白质的标志，可以被激发通过胶水。可能是呃呃，蓝灯在450，呃，413，还有一些蓝灯之后。然后，一旦这个科学 cfp 兴奋起来，他们就可以给我们提供科学，以获取本质。荧光完全可以用来激发贫民窟的一些抗议活动。是的，荧光蛋白。它对cfp的网站感到兴奋，然后他可以模仿，本质上，每小时530美元。这个想法是这样的，呃，你知道，从蛋白质的接穗力到蛋白质的黄色力的共振转移只发生，只发生在真正的蛋白质彼此接近时。所以假设这是青色蛋白质，这是黄色荧光蛋白质，这种，你知道，这种蛋白质的激发，因为事实上，从本质上来说，呃，共振能量转移只有当这种蛋白质连接在一起时才会发生。

So you can imagine when they use the proteins to carry open, this protein is two proteins, is too far as a protein will be moved away from each other. Right? So which means that if you cut the after enzymatic activity, you will this kind of uh so called forest and energy forest resident energy transfer thread will be abolished. So this is actually the experiment, uh, experiment, experiment, experimental data that we use of republic.
所以你可以想象当他们用蛋白质来搬运开来的时候，这个蛋白质是两个蛋白质，距离太远的一个蛋白质就会彼此远离。正确的？所以这意味着如果你切断后酶活性，你这种呃所谓的森林和能源森林居民能量转移线就会被废除。所以这实际上是我们用共和国的实验，呃，实验，实验，实验数据。

So, um, basically, we do experiments where, you know, uh, using a different concentration of protein is 0to4 micro molar inside.
所以，嗯，基本上，我们做实验，你知道，呃，使用不同浓度的蛋白质，里面是 0 到 4 微摩尔。

So and then we try to excite this protein in the beginning. I put the protein diffusion protein to the, you know, to the uh, to the assay, to, and then the if you don't, and then we excite the um, uh, this protein with the with 430nanometer.
因此，我们一开始就尝试激发这种蛋白质。我将蛋白质扩散蛋白放入，你知道，呃，进行测定，然后，如果你不这样做，然后我们用 430 纳米激发嗯，呃，这种蛋白质。

And then we try to solve then any uh, if there's any uh fluorescence at five, 30. So if you do not add inside, which is actually just for supply, okay, basically, you know, it doesn't change a lot. Okay, that would indicate the film remain stable, okay, without you know, without addition to projects. But if you add projects, for example, like for micro molar broken, which is like this online. Thank you. All right. So we I think. Do you want an option? Please resume. And the good news about this. We can we can even measure the rate of the reaction.
然后我们尝试解决任何呃，如果有任何呃荧光在 5、30 处。所以如果你不添加到里面，这实际上只是为了供应，好吧，基本上，你知道，它不会改变很多。好吧，这表明这部电影保持稳定，好吧，在你不知道的情况下，没有增加项目。但是如果你添加项目，例如，像微磨牙破碎，网上是这样的。谢谢。好的。所以我们我认为。你想要一个选择吗？请恢复。关于这一点的好消息。我们甚至可以测量反应速率。

Ok. I think you if you if you did the lab in 62thousand, you measure the the magic activity of a effort for is, oh, yeah, I got it. And basically, we do 2point, but at that time, you only do two type on zero. And then 1minute, right? But this is what we call quite proper. We we do a lot of, you know, time over a lot of uh, this is, you know, is something willing to take 2point. We talked a lot of time point and measure before essence. And and this is saying is also uh, quite good because uh, and we used it in the so called 96 well played format as a high throughput for screening drugs.
好的。我想如果你做了 62000 的实验室，你测量了一项努力的神奇活动，哦，是的，我明白了。基本上，我们做 2point，但那时，你只在零上做两种类型。然后1分钟，对吧？但这就是我们所说的非常正确的。我们做了很多，你知道，时间超过了很多呃，这是，你知道，是愿意拿2分的事情。在本质之前我们讲了很多时间点和措施。这就是说，嗯，非常好，因为嗯，我们在所谓的 96 场比赛格式中使用它作为筛选药物的高通量。

Okay, um. In fact, I did not use it to to spin drop. In fact, I use it to look at the uh substrate specificity of the uh source main produce. The idea is, you see, this is the native sequence, one of the native sequence for the um sars proteins, which have a sequence of s at the p five sablg okay, g is actually at the p one positions. And then this is a sisal bond and the p one prime persistence and so on. Um, you have the sgs so on. So what I did was to create a library that have a combination of all, even as a combination. So basically, ii introduce mutation at every, so you got I focus on on 18 an acid. And for eating acid, okay, I introduce a 19intention, but there are only 20masses, right? So if you maintain 19intention, basically try all of the possibility. So in this case, I create a substrate library of uh19 mutation for an in position. Basically, you've got a lot of uh uh mutations. And then uh we measured and semantic and semantic activities of the protests from uh for uh different kinds of virus. Again, each of this library.
好吧，嗯。事实上，我并没有用它来旋转掉落。事实上，我用它来查看呃源主要产品的呃底物特异性。这个想法是，你看，这是天然序列，um sars 蛋白的天然序列之一，它在 p 5 sablg 处有一个 s 序列，好吧，g 实际上在 p 1 位置。然后这是剑麻键和p一素数持久性等等。嗯，你有 sgs 等等。所以我所做的就是创建一个将所有内容组合在一起的库，甚至作为组合。所以基本上，我每次都会引入突变，所以我重点关注18酸。至于吃酸，好吧，我引入了 19 个意图，但只有 20 个质量，对吗？所以如果你保持19个意图，基本上就尝试所有的可能性。因此，在这种情况下，我创建了一个 uh19 突变的底物库。基本上，你有很多呃呃突变。然后呃我们测量了呃对呃不同种类的病毒的抗议的语义和语义活动。再说一遍，这个图书馆的每一个。

Okay, it's another one. Okay, my student was working quite hard and yeah, and you see, but the good news is because uh, you can always is easy. Um, you can use uh, 96 well played to perform this reaction. And it's not as as tedious as you think. Uh, but anyway, there's a lot of reaction. Okay, uh, I tried a different uh virus, okay, for virus. Okay, there are some of them are from uh alpha or rather two of them from beta. One of them, what is the sars virus? And then the one of them from ghana. Okay, you may ask why I did not try the delta. Delta was not discovered at that time. Okay? But not not was not yet discovered at that time. Otherwise I would have done it. Okay? But at that time it was only three, okay? Alpha. At 2010, it was only 2 hours for beta. Right? At the job.
好吧，这是另一件。好吧，我的学生非常努力，是的，你看，但好消息是因为呃，你总是很容易。嗯，你可以使用呃，96 well Play 来执行这个反应。而且它并不像你想象的那么乏味。呃，但无论如何，有很多反应。好吧，呃，我尝试了另一种呃病毒，好吧，对于病毒。好吧，其中一些来自呃 alpha，或者更确切地说其中两个来自 beta。其中之一，非典病毒是什么？然后是其中一位来自加纳的人。好吧，你可能会问为什么我没有尝试 Delta。当时Delta还没有被发现。好的？但当时并非还没有被发现。否则我就会这么做了。好的？但当时只有三个好吗？阿尔法。 2010 年，测试版只有 2 个小时。正确的？在工作中。

Okay, um, okay, so and then you can see that got a precision from p five, p four, p three, p two, p one, p one prime, p two prime, p three prime, as for each of the uh, for each of the position. I've got uh, 20 possibility, wild type, you know, the wild type sequence+19 units, right? So we've got 20 in the acid. And then these are the so called relative activity. Is if relative activity is equal to one, it means it's the same as the wild type sequence. Okay? And if the sequence is just, you can see, for example, some actually higher than one. Let me see for some of this guy.
好吧，嗯，好吧，然后你可以看到从 p 5、p 4、p 3、p 2、p 1、p 1 质数、p 2 质数、p 3 质数得到了精度，对于每个 uh ，对于每个位置。我有呃，20 种可能性，野生型，你知道，野生型序列+19 个单位，对吗？所以我们有 20 个酸。然后这些就是所谓的相对活动。如果相对活性等于一，则意味着它与野生型序列相同。好的？如果序列是公正的，你可以看到，例如，有些实际上高于一。让我看看这个人的一些情况。

Okay, if you you take uh, substitute positive charge residue at the at the p three position, you can have bracket absolutely higher than one, even stronger than the world. I see. Um. So, so so these are integral messages, okay? About the substrate specificity of and you know, you can probably see that at p five, do you see any trend? Not quite right. They are the the data are actually very noisy. So that actually means that uh, at p five position, the enzyme does not have much presence. But for on the other hand, at human position, the enzyme is actually very picky, right? You can only have activity it made. The best is the native sequence of beauty, right?
好吧，如果你把呃，替换掉p 3位置处的正电荷残基，你就可以拥有绝对比一更高的括号，甚至比世界更强。我懂了。嗯。所以，所以这些都是不可或缺的信息，好吗？关于底物特异性，您知道，您可能可以在第五页看到，您看到任何趋势吗？不太正确。它们的数据实际上非常嘈杂。所以这实际上意味着呃，在第 5 个位置，酶没有太多存在。但另一方面，在人类的位置上，酶实际上是非常挑剔的，对吗？您只能拥有它所做的活动。最好的就是美丽的自然序列，对吗？

Q uh, maybe a little bit of histidine, maybe even weaker for the signing before less of the massive or no. Right? So very specific appeal decisions. P two is also quite specific. You look into this, right? A lot of them in the acid cannot function, maybe except some hydro large hydrogel residue like using the dining and phenomenon. Um, p for it will be perfect. There's still someone as it cannot work, maybe some would work. And so some clear preference for smaller hydrophobic residues like allen and bailey. And for pure prime position, probably also see some trend who favor some small and acid like aligon, lysine series, and 60 p two, I don't see much preference, maybe except it doesn't like protein, but can do that. But for most of the other in acid, you you don't see a very clear trend. Chen the same also applied to be three part, okay? Don't have a strong preference.
问：嗯，也许有一点组氨酸，在减少大量组氨酸或没有组氨酸之前，对于签名可能会更弱。正确的？所以非常具体的上诉决定。 P二也很具体。你调查一下这个，对吗？它们中的许多在酸中无法发挥作用，也许除了一些水大的水凝胶残留物，如使用餐饮和现象。嗯，p 因为它会很完美。仍然有人无法工作，也许有些人可以工作。因此，人们明显偏爱较小的疏水性残基，例如艾伦和贝利。对于纯粹的黄金位置，可能还会看到一些趋势，他们喜欢一些小的和酸性的，如 aligon、赖氨酸系列和 60 p 2，我没有看到太多的偏好，也许除了它不喜欢蛋白质，但可以做到这一点。但对于大多数其他酸，你看不到非常明显的趋势。陈同样也申请了三部曲，好吗？没有强烈的偏好。

Now remember this, so this is the basic science talk about how enzyme would recognize is substrate. So the take a message is probably p one specific, right? Uh, the position that especially maybe p one is the most specific position, may be followed by p two, right? And then to a certain extent, p four, p one, and p three. But p one, p two prime, p three prime, p five prime, and less important, right? Compare to these enzyme structure is specific, right? Do you do you agree? It's my research. Okay, I thought I have to agree. You don't have to agree with me. But but but this is this is this is what I saw. So now, if you go back to compare the sequence, what are the names? What are the viral sequence of that? Remember, the proteins are going to catch the contract category protein into, you know, 16, all these, uh, as before 2016. So then then would they the the sequence that are recognized by the native virus sequence actually summarize in this so called a sequence logo representation.
现在记住这一点，这是关于酶如何识别底物的基础科学讨论。所以接收消息可能是特定的，对吧？呃，尤其可能p一是最具体的位置，后面可能是p二，对吧？然后到了一定程度，p四，p一，p三。但是p一、p二素数、p三素数、p五素数，不太重要，对吧？相比之下这些酶的结构是特定的，对吗？你同意吗？这是我的研究。好吧，我想我必须同意。你不必同意我的观点。但是但是但是这就是这就是这就是我所看到的。那么现在，如果你回去比较序列，名字是什么？它的病毒序列是什么？请记住，这些蛋白质将把合同类别蛋白质捕获到，你知道，16 个，所有这些，呃，就像 2016 年之前一样。那么它们将被天然病毒序列识别的序列实际上总结为这个所谓的序列标志表示。

Okay, so these are the sequence variation within the viral genome. Okay? Can you argue that this is something you artificial? Yeah, this is something you see in the in the laboratory. So this is actually what happened. If you compare to some fine dramatics, compare the sequence of the counting sequence, then you also find a very similar conclusions where if you look at the privacy, the cutting side always has a huge right at p one.
好的，这些是病毒基因组内的序列变异。好的？你能说这是你人为的吗？是的，这是你在实验室里看到的东西。这就是实际发生的事情。如果你对比一些精品剧，对比计数序列的顺序，那么你也会发现一个非常相似的结论，如果你看隐私的话，剪边总是在p一处有一个巨大的权利。

Okay, okay, let me explain. So this is uh, we just try to look at the occurrence of the acid at which of the position. If the logo is bigger, it means that that it has a higher, higher chance of occurrence. For example, this one, you see, the queue is so bad, right? The only thing queue, right? Which means that at p one possession of the native ram sequence, you only see a uterine human, right? And for peter possession what you see? L right? L is also coincide with what I observe experimentally. Okay? So l may be also m refining main. Uh, it goes. So alice, l is is the most prefer, right, uh, uh, sequence in developing them. And, uh, maybe, again, for p one prime, again, small rights, syrian ali, both these two are the has the highest occurrence in the sequence. And again, it also coincide with the experimental observation that enemy and series, they they are preferred ok in the eps and other activities.
好吧好吧，让我解释一下。所以这是呃,我们只是尝试看看酸出现在哪个位置。如果标志越大，则意味着它出现的几率越高。比如说这个，你看，排队的情况这么糟糕吧？唯一的事情就是排队，对吗？这意味着当你拥有本地公羊序列时，你只能看到一个子宫人类，对吗？对于彼得的占有，你看到了什么？对吗？ L也与我的实验观察结果相符。好的？所以l可能也是m炼主。呃，它过去了。所以爱丽丝，我是最喜欢的，对的，呃，呃，开发它们的顺序。而且，呃，也许，再次，对于 p 素数，再次，小权利，叙利亚阿里，这两个都是序列中出现次数最高的。再次，这也与敌人和系列的实验观察相吻合，它们在 eps 和其他活动中是首选。

And for other, you don't see a lot of sequence standard clearly, but probably the take a messages, if you want to decide an inhibitor that would inhibit the enzyme, probably something like it, losing ap two position, something like apup uh, uh, you to me at ap one position, something small and people crying. If you can do that, um would be a good selling.. Yeah, if you don't know what i'm talking about of its 20 amino acid, what is a kill? Okay, um. Um, if you study some biology, you should have learned in year one or year two. But but this is the don't know where so this is the um, quick q card. I copy from wikipedia which tell you the revision of the 20 m assets and the and the structure.
对于其他的，你看不到很多序列标准，但可能会收到一条消息，如果你想决定一种抑制酶的抑制剂，可能是类似的东西，失去 ap 两个位置，比如 apup 呃呃，你对我来说是一个位置，一件小事，让人哭。如果你能做到这一点，那么销量会很好。是的，如果你不知道我在说什么它的 20 种氨基酸，那么什么是杀戮？好吧，嗯。嗯，如果你学习一些生物学，你应该在第一年或第二年就学会了。但这是不知道在哪里所以这是嗯，快速q 卡。我从维基百科复制过来，它告诉你 20 m 资产和结构的修订。

Okay, uh uh, for and I also call them by their uh their property, for example, hydrophobic residue accounting in orange, uh, for negative charge residue, the color in the light blue. For past for for negative positive charge residue, there are in blue for negative charge residue as the rest of the color in in the what's this color? Red, no, jackson or purple. And for those, the polar residue, when that neutral polar residue, that color is green. So, uh, so, and again, you see, once take a message from the colorado studies, it recognized the most important residue that are required for catalysis, for the protest activity that we need you to be of q at the key one positions.
好的，呃呃，我也用它们的性质来称呼它们，例如，疏水性残基为橙色，呃，负电荷残基，颜色为浅蓝色。对于过去的负电荷残留物，有蓝色的负电荷残留物，其余颜色在这个颜色是什么？红色，不，杰克逊或紫色。对于那些极性残基，当中性极性残基时，颜色是绿色的。所以，呃，所以，再一次，你看，一旦从科罗拉多州的研究中得到信息，它就认识到催化所需的最重要的残留物，对于我们需要你在关键位置的抗议活动。

And luckily, no, no human projects would recognize the same thing as a resident. No, no, human protests would recognize. That's you to be mentioned, which means that if you can develop a inhibitor that would target the main proteins, is side effect on cutting up the offside target would be low.
幸运的是，不，没有任何人类项目会识别出与居民相同的东西。不，不，人类的抗议会承认。这就是你要提到的，这意味着如果你能开发出一种针对主要蛋白质的抑制剂，那么切断越位目标的副作用就会很低。

On the other hand, there's another protest. You still remember. This is actually two proteins. There's another protest call, sorry, called the pine light produce or plp it shares a substrate specificity of another enzymes, uh, called human be used to quit, to be acquaintance. Okay? And and and which means that people don't look into developed, developed the developing drug that will inhibit this enzyme. Even if you can find a drug that inhibit this enzyme, the drug can also inhibit your human enzyme that will cause a lot of side effect.
另一方面，还有另一种抗议。你还记得。这实际上是两种蛋白质。还有另一个抗议呼吁，抱歉，称为松光产物或 plp，它与另一种酶具有底物特异性，呃，称为人类习惯戒烟，习惯结识。好的？这意味着人们不会研究开发、开发能够抑制这种酶的药物。即使你能找到抑制这种酶的药物，该药物也会抑制你人体的酶，从而引起很多副作用。

Okay. So the drought uh, that developed by the company advisor belongs to a group of drug drug call, had to do me magic. Candida means is the peptide. The magic is mimic um, that create drugs that look like that looks like a peptide. So that's called had been dominating droughts, had this only magic inhibitor, a drugs that they made that looks alike. And it has time. So the basic design of it at the dominic are inhibitor. It's actually not too difficult to comprehend. So assuming so remember, so this is the uh the schematic diagram I drew or I drew uh several slide ago talking about how enzyme would recognize the substrate, the protein substrate. Remember, during that discussion, I mentioned there are several pocket on the enzyme substrate binding pocket that was involved in interacting with the substrate. They are called s one, s two, s four, s one prime, s two prime.
好的。所以干旱呃，由公司顾问开发的属于一个药物组的药物呼叫，不得不给我带来魔力。念珠菌的意思是肽。神奇之处在于模仿，它可以创造出看起来像肽的药物。这就是所谓的主宰干旱，有这种唯一的神奇抑制剂，一种他们制造的看起来很相似的药物。而且有时间。所以多米尼克的基本设计是抑制剂。其实并不是太难理解。所以假设如此，请记住，这就是我画的示意图，或者我在几张幻灯片之前画的，讨论酶如何识别底物，即蛋白质底物。请记住，在那次讨论中，我提到酶底物结合口袋上有几个口袋参与与底物的相互作用。它们被称为s一、s二、s四、s一素数、s二素数。

Okay, so, in fact, the pet, the dominic inhibitor take advantage of these structural features of the enzymes to create a drug that would mimic at times, but at times. Okay? Uh, but for example, this one. So you have uh, so this is uh, oh, thank this is a this is the inhibitor that I uh uh then I work on. Okay, so so so this is uh basically you you start with uh you basically you have a peptide sequence. Okay? And then if you are putting uh, putting chemistry, so this is a cube to the means. And this is the new scene that are recognized by. Basically, you basically you cut this, you cut this part, you cut this. Basically this is so great, right? It's a peptide substrate. And then at one end, okay, ii did it at the end of the peptide. And then you put a so called warhead. What that means is the chemical functional work that can react with the active site residue, sixty one four fiveand inactivate. So this is what happens to the one that q centers and then is followed by a peptide called a capital magic part that would mimic.
好吧，事实上，宠物，多米尼克抑制剂利用酶的这些结构特征来创造一种有时会模仿的药物，但有时。好的？呃，举个例子，这个。所以你有呃，所以这是呃，哦，谢谢，这是我呃呃然后我研究的抑制剂。好吧，所以这就是呃基本上你开始了呃你基本上你有一个肽序列。好的？然后，如果你投入呃，投入化学反应，那么这就是方法的立方体。而这就是大家所认可的新场景。基本上，你基本上你剪了这个，你剪了这个部分，你剪了这个。基本上这太棒了，对吧？它是一种肽底物。然后在一端，好吧，我在肽的末端做了这件事。然后你放了一个所谓的弹头。这意味着化学功能性工作可以与活性位点残基发生反应，六十一四五并失活。所以这就是以 q 为中心的那个发生的情况，然后后面跟着一个被称为大写神奇部分的肽，它会模仿。

Okay, that looks like what is in this case, it's not look like. Basically, it's just copy and paste the plagiarized from the substrate, okay? That that are found in the virus sequence. And then typically, on the other, on one hand, on on this enemy, on the one hand, on the other end of the of this attempt to dramatic drops. You have a protective group. So basically, the basic design of basic component of a doblematic drug is you have a warhead. Okay? That functional good that kills them, they can react with the essence, a peptide or that. It will be many part that would that would allow the drug to bind effectively to the substrate binding site on enzymes.
好吧，看起来就像这个例子中的情况，但事实并非如此。基本上，它只是从基材上复制并粘贴抄袭的内容，好吗？在病毒序列中发现的。然后通常，另一方面，一方面，这个敌人，一方面，另一方面，这种尝试的另一端急剧下降。你有一个保护团体。所以基本上，双药药物基本组件的基本设计是有一个弹头。好的？那些杀死它们的功能性物质，它们可以与精华、肽等发生反应。许多部分将使药物有效地结合到酶上的底物结合位点。

And then also a protective growth, ￡3, protective growth at the dramatic part that bind to the substrate binding side of the inside. And then the one byebye. Yeah. And um, well, again, oh, this is my last paper on this subject. Okay? Uh. I am not the last the second answer. Okay? Ii did publish something for open. Um, so this one is again, this is published in 2013 about some you know, the sign of some drugs. Okay, um, um, that would inhibit the enzymes.
然后还有一个保护性生长，3英镑，保护性生长在与内部的底物结合侧结合的显着部分。然后就是再见了。是的。嗯，好吧，再次，哦，这是我关于这个主题的最后一篇论文。好的？呃。我不是最后一个第二个答案。好的？我确实发布了一些开放的东西。嗯，这又是一篇，这是 2013 年发表的，关于一些你知道的、一些毒品的标志。好吧，嗯，嗯，这会抑制酶。

So again, so these are ii do a lot of the different design. For example, this one either are designed a peptide with the sequence of iron baby using, uh, uh, uh, due to me, this is a peptide sequence. We got the protective group. Cn is this night travel for the warhead. And then the in this case, in order to after you make some inhibitor, then you want to do some in some assay to see the weather that compound that you may can inhibit the enzyme. So this is the, uh, so called the enzyme assay. So typically is something like this. So basically, you mentioned and symmetric activity, um, in this case, where it can be relatively limited, uh, relatively, uh, uh, granted activity. If this is one equals two, which means the activity is the same as the enzyme without with no inhibitor. One one hundred%. Okay?
再说一次，我做了很多不同的设计。比如这个要么是用铁宝贝的序列设计一个肽，呃呃呃，对我来说，这是一个肽序列。我们得到了保护组。 cn就是这个夜行的弹头。然后在这种情况下，为了在你制造一些抑制剂之后，你需要做一些实验来看看你可以抑制酶的化合物的情况。这就是，呃，所谓的酶测定。通常是这样的。所以基本上，你提到了对称活动，嗯，在这种情况下，它可以是相对有限的，呃，相对，呃，呃，理所当然的活动。如果一等于二，则表示酶的活性与不加抑制剂的酶相同。百分之一百。好的？

So if you increase and then face, typically you you repeat the experiment by increasing the concentration of the inhibitor from maybe in this game with one micro order to something like, uh, you know, this is, I think, several, 1 or 201 23 around 250, uh, uh, 215, michael molar. And then and then you measure the in the the the enzyme activity of the proteins, in the presence of different concentration. You can imagine the activity go down when you increase inhibitor. That's obvious, right? If you and more and more independent of the reaction, the enzyme activity goes down. A typical this kind of this kind of a graph were plotted as a long concentration that normally implied the concentration of the inhibitors a lot. You see, this is a lot. And then the and then the shape of the living in the in the inhibition code will always look like like s shapes and models. And here we would like to mesh, typically how to quantify how potent your inhibitor is is measured by a valuable ic 50, that the intimate concentration, the inhibitor concentration, that gives you 50% inhibitions.
因此，如果你增加然后面对，通常你会通过增加抑制剂的浓度来重复实验，从可能在这个游戏中用一个微命令增加到类似，呃，你知道，这是，我认为，几个，1或201 23 250 左右，呃，呃，215，迈克尔·摩尔。然后测量不同浓度下蛋白质的酶活性。您可以想象当您增加抑制剂时活性会下降。这很明显，对吧？如果反应越来越独立，酶的活性就会下降。典型的此类图表被绘制为长浓度，通常暗示抑制剂的浓度很多。你看，这已经很多了。然后，然后，在抑制代码中生活的形状将永远看起来像s的形状和模型。在这里，我们想要进行网格划分，通常如何通过有价值的 ic 50 来测量抑制剂的效力，即提供 50% 抑制作用的密切浓度（即抑制剂浓度）。

So typically, the the physical meaning of this, uh, ic 50 is so so without inhibitor, you've got 100% activity with with very with very, very high concentration. You've got zero, right, basically completely different things. And then ic 50 is somewhere the concentration of the inhibitor that gives you 50% half of the inhibition. Make sense?
所以通常情况下，这个，呃，ic 50 的物理意义就是如此，没有抑制剂，你就可以在非常非常高的浓度下获得 100% 的活性。你有零，对，基本上完全不同的东西。然后 ic 50 是抑制剂的浓度，可以提供 50% 的一半抑制。有道理吗？

Okay, oh, so this call I see it a little bit of concentration to achieve 50% population. Ok so, so, for example, here iii compared to inhibitor. So this is an inhibitor with only four in acid, with the same forehead. And this guy, this guy, has1234566. I mean, as a as a part time, happy, dramatic, and also have. And then you can measure for this guy, uh, the ic 50, you can do it this term going down here. It will be equal to 4.6 micro molar. And for this guy, which is under this curve, and then the ic 50, you go through it down. Here is over here, would be around 39. I don't know. So, can I ask you one question? Which one is better? Thank you. Which one is more potent? A stronger inhibitor, this guy or that guy. Thanks. This guy, raise your hands on the view of the second. Okay? How about this guy?
好吧，哦，所以这个电话我认为它有点集中，以达到 50% 的人口。好的，所以，例如，这里 iii 与抑制剂进行比较。所以这是一种只有四个酸的抑制剂，具有相同的前额。而这个家伙，这个家伙，有1234566。我的意思是，作为一个兼职，快乐的，戏剧性的，也有。然后你可以测量这个家伙，呃，ic 50，你可以在这个学期在这里进行。它将等于 4.6 微摩尔。对于这个位于这条曲线下方的家伙，然后是 ic 50，你会经历它。这里是这里，大约是 39。我不知道。那么，我可以问你一个问题吗？哪一个更好？谢谢。哪一种更有效？更强的抑制剂，这个人或那个人。谢谢。这家伙，请在第二个视图上举手。好的？这个人怎么样？

Okay, so obviously, the number smaller is more potent. That makes sense, right? You use smaller amount of inhibitor to achieve the same 50% innovation, right? So you want small, okay? Michael molar, if you look at the drug company is not very good, you need to talk about nano molar, okay? So but this is for your research, okay? But uh yeah. Okay, so and and all a little of my own research, okay, ii so the best and then probably I find out this is the passive emitter. I actually did. 1235. Ii we made I made four and then this one is the best.
好吧，很明显，数字越小，效力越强。这有道理，对吧？您使用更少量的抑制剂即可实现同样 50% 的创新，对吧？所以你想要小一点，好吗？迈克尔摩尔，如果你看制药公司不是很好，你需要谈谈纳米摩尔，好吗？但这是为了你的研究，好吗？但是，呃，是的。好吧，我自己的一些研究，好吧，所以最好的，然后我可能会发现这是无源发射器。我确实做到了。 1235. 我们做了四个，然后这个是最好的。

And then I tried it on the different uh viruses. Okay, remember, one advantage of this peptide, a protest inhibitors that one of the advantage that it is actually brought special. Right? Because the proteins from alpha, beta, gamma virus is so similar. I did not have got delta at that time. So only test, uh, I test a lot of different uh viruses, okay? These two guys are out belongs to the alpha corona virus. Okay? And these two guys, this 123 are belong. They belong to the beta version. And this is the gamma worship. And then top, and then I add this, uh, and and then I make the main proceeds from all these six virus, uh, virus viruses.
然后我在不同的呃病毒上进行了尝试。好吧，请记住，这种肽的一个优点是，它是一种抗议抑制剂，它的优点之一实际上是特殊的。正确的？因为α、β、γ病毒的蛋白质非常相似。我当时还没有Delta。所以只测试，呃，我测试了很多不同的呃病毒，好吗？这两个人都属于甲型冠状病毒。好的？而这两个家伙，就是属于这个123的。它们属于测试版。这就是伽玛崇拜。然后顶部，然后我添加这个，呃，然后我的主要收益来自所有这六个病毒，呃，病毒病毒。

And then the and then I add this uh, a little bit. And then you find that all of them is that, for example, in the similar micro mode, they all have inhibition and around2~4. Michael motor, I see 50. Which means that the the pack the the the the the inhibitor that that I made is prospection. Right? In case the virus get any you you talk about across alpha to gamma, okay? I suspect you also work on delta, but I did not check, okay? There was there was no doubt of virus at that time. Uh, the the reason, as I said, because this sequence is actually originated from the sequence similarity. The substrate, specifically, they all share. You know, they need to come as a cube and they always prefer using ap two position. For all six riders. They all have the very similar uh substrate specificity. Okay, if you have similar subject specificity, if your inhibitor are look alike a we may try to mimic the the um the the uh the substrate, then chance of that has got very prospect from activity which is actually showing you.
然后然后我添加这个呃，一点点。然后你发现它们都是，比如说类似的微模式，它们都有抑制作用，在2~4左右。迈克尔马达，我看到50。这意味着我制作的抑制剂包是勘探。正确的？万一病毒感染了你所说的从阿尔法到伽马的病毒，好吗？我怀疑你也在 delta 工作，但我没有检查，好吗？当时毫无疑问存在病毒。呃,这个原因,我已经说了,因为这个序列其实是源于序列的相似性。具体来说，它们都共享基板。你知道，他们需要以立方体的形式出现，而且他们总是更喜欢使用两个位置。对于所有六名车手。它们都具有非常相似的底物特异性。好吧，如果你有类似的主题特异性，如果你的抑制剂看起来很相似，我们可能会尝试模仿底物，那么从实际向你展示的活动中，这种可能性就非常有前景。

Okay. So I guess uh, probably I would like to stop here for a short break and then for in a warhead. So when people decide the warhead of a uh, inhibitor, there are actually two types. Okay, uh, one type. Well, all of them are chemical worlds or fat functional world. Um, that would react with the um, the active site residue, 16, 145. Okay. Okay, um. Okay, so for example, I probably I don't go into the chemistry, but they they can be classified into two worlds. One will be, for example, aldehyde and nitride after forming a uh, after reacting with the enzyme, it would actually resulting in a um, enzyme inhibitor complex, where the cysteine 145 would would then confidently, you know, pointed to the had a dramatic part to the rest of the impetus.
好的。所以我想呃，可能我想在这里停下来短暂休息，然后进入弹头。所以当人们决定呃抑制剂的弹头时,实际上有两种类型。好吧，呃，一种。好吧，它们都是化学世界或脂肪功能世界。嗯，它会与活性位点残基 16、145 发生反应。好的。好吧，嗯。好吧，举例来说，我可能不会研究化学，但它们可以分为两个世界。例如，醛和氮化物形成一个呃，在与酶反应后，它实际上会产生一个呃，酶抑制剂复合物，其中半胱氨酸145会自信地，你知道，指出有一个其余推动力的戏剧性部分。

But on and on the second type of the inhibitors. And and for this type of inhibitors, they would uh interact with the for the pathetic magic part we interact with. Typically, uh, enzymes, substrate binding site, s one, s two, s three, and s four, s one two, s four. And there's another type of uh chemical fun form like ketone allocating a noise, or alpha, beta, and saturated acid.
但还有第二种类型的抑制剂。对于这种类型的抑制剂，它们会与我们相互作用的可悲的魔法部分相互作用。通常，呃，酶，底物结合位点，s一，s二，s三，s四，s一二，s四。还有另一种化学有趣的形式，比如分配噪音的酮，或α、β和饱和酸。

After the chemical reactions we we resulting in. Okay, you you in in addition to that automatic part on this part, can also have another chemical group of the output here that can't. Okay, if you design it right, they can have some interactions with the s one prime. Now, uh, a society of the uh, of the uh of the enzymes. So so this is naturally shows you what happened. Okay, uh, some of the inhibitor enzyme complex has been determined by crystal structure. And for example, this this is actually the one I determine. This is the one I did. Ok so, um, I for example, this is a pattern of romantic. We've got cation sequence. Ok this is the protective role. And then you have a uh nine trial as a warhead after reacting with the uh sixty one four five, which is located somewhere here. Okay? And then we see that the peptide, the the patagly matic with meaning the the substrate that would have interaction with the essence of sight as to subside and as possible site. Of course, you cannot interact with the s one prime subside, because uh, uh, it does not have this side of the camp, uh uh, the functional review.
化学反应之后我们就产生了。好吧，你除了这部分上的那个自动部分之外，还可以有这里不能输出的另一个化学组。好吧，如果设计得当，它们可以与 s one prime 进行一些交互。现在，呃，一个呃，酶的社会。所以这自然会向您展示发生了什么。好的，呃，一些抑制剂酶复合物已由晶体结构确定。例如，这实际上是我确定的。这是我做的。好吧，嗯，比如我，这是一种浪漫的模式。我们有阳离子序列。好吧，这就是保护作用。然后，在与位于此处某处的呃六十四五反应后，你会进行呃九试验作为弹头。好的？然后我们看到肽，patagly matic，意味着与视觉本质相互作用的底物，以消退和可能的位点。当然你不能和s one prime subside互动，因为呃呃它没有这边阵营呃呃功能审核。

But on the other hand, this is another example. This is a uh, you know, this is another inhibitor using a alpha, beta, and saturated as the as the warhead. And after after uh, reaction with the uh, active sites in 14, 5. Okay, this part, you see, you've got residues, you got the part that would mimicking as occupied as well as to. And that's all ok so this part would interact with subside, s one to s four. Again, because you've got another work here, which is pointing to that direction that will also occupying the s one prime subside. So if you do a little bit of quick summary, sorry. Okay, there's actually 2 types of chemical growth. Some to one type will give you only on this side of the a social body pocket, and some of the chemical gives you both. Thank you. Oh, oh. So, yeah, so you've got a lot of all these different camera you can choose, people will choose from. Um. Okay, and probably from before the break, hope, I already convince you that one of the very important residues, uh, that recognized by the subside number one is naked.
但另一方面，这又是一个例子。这是一个呃，你知道，这是另一种抑制剂，使用α、β和饱和作为弹头。在呃，与呃，14、5 中的活性位点发生反应之后。好吧，这部分，你看，你有残留物，你得到了模仿被占据和被占据的部分。一切都很好，所以这部分会与沉降相互作用，从一到四。再说一遍，因为你在这里还有另一项工作，它指向的方向也将占据 s 的一个主要消退点。因此，如果您做一些快速总结，抱歉。好吧，实际上有两种类型的化学生长。有些对一种类型只会给你社交身体口袋的这一侧，而有些化学物质会给你两者。谢谢。哦，哦。所以，是的，所以你有很多不同的相机可以选择，人们会从中选择。嗯。好吧，也许从休息之前开始，希望，我已经让你相信，非常重要的残留物之一，呃，被第一个沉降所识别的残留物是赤裸的。

So this is this is actually why this is actually so important or so specific, because for you to me, it has the ai control rule. They might control and actually recognized by the enzyme by forming 200 bonds with one of the two history, 1163. The other to do to make 166 is 200. 1 will be very specific. That would allow it to recognize to do to me and residue at the p one positions. Okay. Um, this, uh, and but glutamine is actually not ideal. A lot of the drug eventually get into the market. Um. They have a slightly different structure. They have a so called a gamma lecture ring. What does it mean? Basically, you can imagine we've got, uh, um, instead of facing a personal structure. But instead, this is instead of having aa my functional peers, get the this bond with an additional additional one, 233covalent bond to make the like is uh, this is a ring five member ring structure.
所以这实际上就是为什么这实际上如此重要或如此具体，因为对于你我来说，它有人工智能控制规则。它们可能通过与两个历史之一形成 200 个键 1163 来控制并实际被酶识别。另一个要形成 166 的是 200。1 将非常具体。这将使它能够识别对我做的事情并残留在 p 1 位置。好的。嗯，这个，呃，但是谷氨酰胺实际上并不理想。许多药物最终进入市场。嗯。它们的结构略有不同。他们有一个所谓的伽玛讲座环。这是什么意思？基本上，你可以想象我们已经，呃，嗯，而不是面对个人结构。但相反，这不是具有我的功能性同位体，而是用额外的一个233共价键得到这个键，以形成类似的呃，这是一个环五元环结构。

Ok that would also would would look like a duty, but it's not due to it, but because um, uh, if you uh, for if you're in a in a drug company forming some way, will also reduce the rotation, will actually get some advantage in terms of uh, in terms of uh, uh, reduce the so called entropy penalty of fighting, also making a little bit bulkier. So they will also better have a better when develops interaction with the s one problem content. Some even do a bigger ring call delta gamma ray. So instead of five number 12345, you can make the ring a little bit bigger to have a so called six number ring, and the six memory, especially called the delta ring. Um, there has been scientists also report using a no, a delta gamma ray. So let the delta a lacto ring, um, as a as a as a surrogate, as a as a as looks, like of the uh um uh due to the messenger of human positions. Uh, I think uh, if you look at the letter that this one is actually very common, okay, more popular, but you also see this guy.
好吧，这看起来也像是一种职责，但这不是因为它，而是因为嗯，呃，如果你呃，因为如果你在一家制药公司以某种方式形成，也会减少轮换，会实际上获得了一些优势，呃，呃，呃，减少了所谓的战斗熵惩罚，也让体积变得更大了一点。因此，他们在与单一问题内容进行互动时也会更好。有些人甚至做了一个更大的环，称为德尔塔伽马射线。因此，除了五个数字 12345，您可以将环做得更大一点，以拥有所谓的六数字环，以及六个存储器，特别称为 Delta 环。嗯，有科学家也报告说使用了一种不，一种δ伽马射线。所以让δa乳环，嗯，作为一个替代品，作为一个看起来，就像呃呃呃由于人类立场的使者。呃,我觉得呃,如果你看信的话,这个其实很常见,好吧,比较流行,但是你也看到了这个家伙。

Now, we move a little bit, now we start our consideration at the warhead. Now, the last slide show about the p one position of the asthma pocket, and then, okay, then we we can think about one more at the s two position. Remember, in the p two position, the most favor residue is, what do you think? Right? Do you think has this kind of structure? Okay, basically, carbon, carbon, 62, ch and then two methods here. So this is a solution. And in fact, the phenomenon is already is already very is already poor. It's by comparing if you replace the losing to a female in the isis, 50 would decrease from0.3 to almost 1.9, right? And and and some people also advocate, uh, instead of using a new thing, some can actually replace the losing with a so called a cyclone whole power. Basically, you you add a bond from here to there. Okay? So so it also very similar to loosen, but you add a common cover for from this company to discover to make it a cycle poor power of group here.
现在，我们稍微移动一下，现在我们开始考虑弹头。现在，最后一张幻灯片显示了哮喘袋的 p 位置，然后，好吧，然后我们可以在 s 2 位置再考虑一个。记住，在p这两个位置上，最受青睐的残基是，你觉得呢？正确的？你认为有这样的结构吗？好的，基本上，碳，碳，62，ch，然后这里有两种方法。所以这是一个解决方案。而事实上，这种现象已经很糟糕了。比较一下，如果你把伊希斯的输给女性，50会从0.3减少到几乎1.9，对吗？而且还有一些人还主张呃,与其用一个新的东西,有的其实可以用一个所谓的旋风整体力量来代替失去的。基本上，你从这里到那里添加了一种联系。好的？所以它也与放松非常相似，但是你添加一个来自该公司的通用封面，以使其成为这里团队的循环贫力。

And this is actually, if you if you look at the uh, they actually also solve the crystal structure of how this guideline to uh, time bind to the uh, as to pocket. So you see, this is the structure of this cycle of this triangle here, which is also very similar to a failing. And icc essentially not much improvement a little bit, um, improve from 0.3 to 0.4 to 4.
这实际上是，如果你看呃，他们实际上还解决了这个指导方针如何呃，时间绑定到呃，就像口袋一样的晶体结构。所以你看，这就是这里这个三角形的这个循环的结构，这也非常类似于失败。而icc本质上没有太大提升一点点，嗯，从0.3提升到0.4再到4。

Okay, so, now, um, i've showed you a lot of the strategy in developed developing a inhibitor for coffee or source code or others actually talking the first two, okay, which is obvious because these two are the most important substrate binding pocket for the main proteins. Now, in the following lecture, I would elaborate a little bit more on the development of hassle of it. Hassle is actually the trade name of the drug. Okay, that are market for treating uh coping 19. I either. Um, what we have covered so far is just, you know, tokyo ic 50, this uh, these are as a magic activity that we do in the product like what you did for alcohol. Hydrogen is on saturday or you know it in the last.
好的，所以，现在，嗯，我已经向您展示了很多开发咖啡抑制剂或源代码或其他人的策略，实际上讨论了前两个，好的，这是显而易见的，因为这两个是最重要的底物结合主要蛋白质的口袋。现在，在接下来的讲座中，我将详细阐述它的麻烦的发展。 Hassle实际上是该药物的商品名。好吧，这就是治疗呃应对 19 的市场。我也是。嗯，到目前为止我们所介绍的只是，你知道，东京 ic 50，这个呃，这些是我们在产品中所做的神奇活动，就像你对酒精所做的那样。周六是氢，或者你最后才知道。

Okay. But having some having a concept, having some compound, that can inhibit the enzyme is only at the very, very beginning of a drug developed development process. So in order to for develop a drug, so this is only give you a starting.of people called a hit or a lead compound for uh, for for a studies. Um. So, probably in the very beginning, you need to identify a the different project, yeah, identify which target. Okay, as I said, target that we are focusing today is the main proteins is enzyme that can start could be a good target for drug development. And then the and then we if you can find some, uh, you can ask me to establish it and semantic assay to measure the ic 15 of whether you compound get intended. The end segmented activity.
好的。但是，拥有某种能够抑制酶的概念、某种化合物只是处于药物开发过程的非常非常开始的阶段。所以为了开发一种药物，这只是给你一个开始。人们称之为“命中”或“先导化合物”，用于呃，用于研究。嗯。所以，可能在一开始，你需要确定一个不同的项目，是的，确定哪个目标。好的，正如我所说，我们今天关注的目标是主要的蛋白质，即酶，它可以成为药物开发的良好目标。然后然后我们如果你能找到一些，呃，你可以要求我建立它和语义分析来测量你的化合物是否符合预期的 ic 15。分段活动结束。

But the fact that the the the compound, the inhibitor can inhibit an enzyme in the testing, doesn't mean it can you can be used to treat humans. There's so many, many steps.
但事实上，该化合物、抑制剂在测试中可以抑制酶，并不意味着它可以用于治疗人类。有很多很多步骤。

The next step people would like to know is whether this drug can inhibit, for example, viral replication using some cell line model. So this is enzyme tested. This file chemistry, except probably some cell bags need to culture cells. Okay? And then to have to see whether the trump will inhabit, okay, this virus replication in the cell based bond. Okay, next, uh, if this is successful, you don't you you still cannot use it on human. Probably you need to ask, okay, animal model to see if you work on mice, rats, even better monkey, right? At those you you you believe, uh, you know, human monkey should be the closest. Okay, relatives in the animal kingdom kingdom that uh, the closest reality to human.
人们想知道的下一步是这种药物是否可以抑制例如使用某些细胞系模型的病毒复制。所以这是经过酶测试的。此文件化学，除了一些细胞袋需要培养细胞之外。好的？然后必须看看特朗普是否会栖息，好吧，这种病毒在基于细胞的键中复制。好吧，接下来，呃，如果这成功了，你不这样做，你仍然不能在人类身上使用它。也许你需要问，好吧，动物模型，看看你是否对小鼠、大鼠，甚至更好的猴子进行研究，对吧？对于那些你你你相信的人来说，呃，你知道，人类猴子应该是最接近的。好吧，动物王国里的亲戚，呃，最接近现实的人类。

Okay? So from biochemistry, as I must say, is to move forward to sell, says the same. And that even animal model, so we call this all these the clinical study. So after we collect all these data, they're all promising that probably you can the applied to the government to, okay, maybe I can try to uh, use it on human. Right? And then we start to a so called clinical far uh clinical trial. Uh, typically, nowadays, the chemical trial has three faces. Three faces. Uh, the grooming picture is, even if you start your compound, when you said you have already spent millions of dollars develop this compound, and then uh you go in, you very okay, everybody is excited, you go to the clinical child phase, number one, the chance.
好的？因此，正如我必须说的那样，从生物化学角度来看，是向前推进销售，同样如此。甚至动物模型，所以我们称之为临床研究。因此，在我们收集所有这些数据后，他们都承诺，也许您可​​以向政府申请，好吧，也许我可以尝试呃，将其用于人类。正确的？然后我们开始进行所谓的临床临床试验。呃，通常来说，现在的化学试验有三个方面。三张面孔。呃,修饰的画面是,即使你开始你的化合物,当你说你已经花了几百万美元开发这个化合物,然后呃你进去,你很好,每个人都很兴奋,你进入临床儿童阶段，第一，机会。

Okay? So this is statistics uh uh, got from the last 10 years from 20, 2011 to 2020. Okay, um, there's some some report. The successful rate from hit cultural one to finally go for market is only less than 80%. Okay, that's why drug development is so expensive. It's so so expensive. Ok so for chemical child one, you you call you you recruit a small a small number of volunteers. Okay? Um, they could be healthy is something that how healthy people then and then the main purpose of the clinical trial phase of robot is sending. Okay, it doesn't ask for, does it why? It doesn't? It doesn't it okay for face child uh for face number one? It's not that many, many issue as you request some volunteer to see if they die. Okay, oh, no, if they die, of course, you know, if they have any serious side effect is the same. And then to check the dosage, okay, probably we could. Uh, they they typically healthy patients and people, and then the you give them different the dosage of drug based on your estimation, from the animal study that something can go wrong uh, in history.
好的？这是从 2011 年 20 日到 2020 年过去 10 年的统计数据。好吧，嗯，有一些报告。从热门文化到最终走向市场的成功率只有不到80%。好吧，这就是药物开发如此昂贵的原因。真是太贵了。好吧，对于化学儿童一号，你称你为招募一小部分志愿者。好的？嗯，他们能够健康是人们当时如何健康然后机器人临床试验阶段的主要目的。好吧，它不要求，这是为什么？不是吗？脸孩子呃脸一号不好吗？这并不是很多很多的问题，因为你要求一些志愿者看看他们是否死了。好吧，哦，不，如果他们死了，当然，你知道，如果他们有任何严重的副作用也是一样的。然后检查剂量，好吧，也许我们可以。呃，他们通常是健康的病人和人，然后你根据你的估计给他们不同的药物剂量，从动物研究来看，历史上可能会出问题。

Of course, if someone can go on, they will go on to go wrong. In some cases, I can tell you some chemical trial, you know, some some subject, you know, some people die by a serious side effect. That's no, sorry. Okay. Okay? Billions or billions of dollar waste. So if you're lucky, your your drug, you know, uh, it's safe and then use the face trial. Uh, you know, child face to test the dosage and then okay, you can then then go to a clinical child phase number two, phase trial number two.
当然，如果有人能继续下去，他们就会继续出错。在某些情况下，我可以告诉你一些化学试验，你知道，一些主题，你知道，有些人死于严重的副作用。那不是，抱歉。好的。好的？数十亿或数十亿美元的浪费。所以，如果你幸运的话，你的药物，你知道，呃，它是安全的，然后使用面部试验。呃，你知道，孩子脸上要测试一下剂量，然后好吧，然后你就可以去临床儿童第二阶段，第二阶段试验。

Now we can start to ask the question whether your drug can effectively cure the disease or treat the disease. Again, for for trial phase number two, you recruit a small group of people, less than 100, tens, several, you know, uh, less than 100. Uh, um. And and then basically, and then you you you try a very small, and then you also test the efficiency, whether the whether the drug works, ok and then you also need to observe if the patients have developed any, like on any side effect, nuisance, and other headache or whatever.
现在我们可以开始问你的药物是否能有效治愈疾病或治疗疾病。再说一遍，对于第二阶段的试验，你招募一小群人，不到 100 人，几十人，几个，你知道，呃，不到 100 人。呃，嗯。然后基本上，然后你你你尝试一个非常小的，然后你还测试效率，药物是否有效，好吧，然后你还需要观察患者是否出现任何副作用，例如任何副作用、滋扰和其他头痛或其他什么。

Okay? If this is uh, promising, if you show some efficiency, basically need to do some statistics is a significant improvement, um, over a flexible control. And then you go into phase number three. Basically, phase number two and phase number three are very similar in this. In in terms of the question, you're also asking the same question, whether you drop its, uh, is it is about, I also observe uh uh efficacy, but in the face of a free, you now to expand the clinical trial to hundreds, if not thousands of patients to collect enough statistics and it's also very, very expensive.
好的？如果这是呃，有希望的话，如果你表现出一些效率，基本上需要做一些统计就是一个显着的改进，嗯，超过了灵活的控制。然后你进入第三阶段。基本上，第二阶段和第三阶段在这方面非常相似。就问题而言，你也在问同样的问题，你是否放弃它，呃，是关于，我也观察呃呃疗效，但是面对免费，你现在要扩大临床试验向数百甚至数千名患者收集足够的统计数据，而且费用也非常非常昂贵。

Okay? It's very expensive. Okay? And and and and if everything's go, go go, all right. Okay, if they, well, no serious side side effect, okay, uh, acceptable side effect nobody die. And at the end of day instead check out the statistics, okay, okay, you see that no drop? Okay, catch some improvement, okay, come for those patients who take the drug, they may be had recovered earlier. They don't have a less chance of going to serious complications and compared to a placebo growth which basically they they think they have taken the pill, but it's actually a placebo. You know it was a place is something you know look like a droplets has no active ingredient.
好的？它非常昂贵。好的？如果一切顺利，那就去吧，好吧。好吧，如果他们，好吧，没有严重的副作用，好吧，呃，可接受的副作用没有人会死。在一天结束时查看统计数据，好吧，好吧，你看到没有下降吗？好吧，找点好转吧，好吧，那些吃药的病人来吧，可能会早点康复。与安慰剂相比，他们出现严重并发症的机会并没有减少，基本上他们认为自己服用了避孕药，但实际上它是安慰剂。你知道那是一个你知道的地方，看起来就像是没有活性成分的水滴。

Okay? And if everything is okay, then you apply to uh the government uh in the america is the the food fda the food and drug administration, and then it is uh oh, okay, has marketed, um, you know, you can go for the market. So you see, so this is aa little bit of story. For example, this is the very initial story, initial compound that identified by pfizer, ok in the in the uh atv aside. And then they have to do a lot of modification before we go to the clinical trial. So from a pocket application to be clinical trial, use the animal model, use the same model, you should answer the same to do a lot of iteration.
好的？如果一切正常，那么你向呃政府申请呃在美国是食品FDA，食品和药物管理局，然后它呃哦，好的，已经上市了，嗯，你知道，你可以去找市场。所以你看，这只是一个小故事。例如，这是最初的故事，辉瑞确定的最初化合物，可以放在呃亚视旁边。然后在我们进行临床试验之前他们必须做很多修改。所以从袖珍应用程序到临床试验，使用动物模型，使用相同的模型，你应该回答相同的问题，进行大量的迭代。

Okay, and then I know you think this one is the is the heat. Before you know the answer, right? You you spell already. I'm just millions of millions of dollar, you know, working on, you know, modifications of this compound so that it has less necessity, you know, uh, using animal model. Okay, uh uh uh less uh less necessity, high efficacy. And then what they come up with is this and this compound call, they call it the the metaphor. And in fact is hong kong. After you go in the clinical trial, it's already is like a the company has to make a decision, I bet on this. Okay. So this is the compound I want to test for clinical trial, and then and then pray to the world. Yeah, yeah, this is actually what it is. Of course, you can say they are experienced. They thought, you know, they have a lot of other. And and this is actually the initial compound in the the the so called the initial hit. And then after a lot of optimization, this is the final compound that he that they sell itself. Good. So cell base.
好吧，我知道你认为这就是热点。在你知道答案之前，对吗？你已经拼写了。我只是花费了数百万美元，你知道，正在研究，你知道，修改这种化合物，以便减少它的必要性，你知道，呃，使用动物模型。好吧，呃呃呃少一点，必要性高，功效高。然后他们想出了这个和这个复合调用，他们称之为隐喻。而事实上就是香港。进入临床试验后，公司就必须做出决定，我敢打赌。好的。所以这就是我想要进行临床试验的化合物，然后向世界祈祷。是啊是啊，实际上就是这样。当然，你可以说他们经验丰富。他们认为，你知道，他们还有很多其他的。这实际上是所谓的初始命中中的初始复合。然后经过大量的优化，这就是他们自己出售的最终化合物。好的。所以细胞基础。

Okay, I think uh in the before the break, I always shows you how you know this uh scientist or this drug company or pharmaceutical company use enzymatic acid, right? It's is the end of just power cap. It has to and makes that up the line is using some cell line, some cell based experiment. So, uh, this is essentially one of the uh, quite the company used to sell the experiment. So you use a uh uh, cell, a culture. Uh, humans are not necessarily human cells, are mammalian cells. Okay? And then, for example, this is a viral cell um, that would express the cell surface receptor, uh, don't uh, so called aaac two positive cells. So a cell that can be infected by the virus. Okay? And after and then you, in fact, the the the this process of the cell is virus out with the uh, with the virus. Okay? And then you test whether and then you repeat the experiment by adding no drug, 1234, 10micro order of drug. You have a you know, you basically increase the concentration of drug.
好吧，我想呃在休息之前，我总是向你展示你如何知道这个呃科学家或这个制药公司或制药公司使用酶酸，对吧？这是权力上限的结束。它必须使用一些细胞系，一些基于细胞的实验来弥补这一点。所以，呃，这本质上是一家呃，相当不错的公司用来销售实验的公司之一。所以你使用呃呃，细胞，一种培养物。呃,人不一定是人类细胞,是哺乳动物细胞。好的？然后比如说这是一个病毒细胞嗯,它会表达细胞表面受体,呃,不要呃,所谓aaac二阳性细胞。所以一个可以被病毒感染的细胞。好的？然后你，事实上，细胞的这个过程就是病毒，呃，病毒。好的？然后你测试是否，然后你通过不添加药物、1234、10微量级的药物来重复实验。你知道，你基本上增加了药物的浓度。

And then to look at the uh, in fact, of the drug on the you can do a lot of apartments for someone can look at the viral replication or in this case look at how will the cell survive, right? So use a cell line. If if your compound can inhibit the viral replication, the cell should be, you know, if you have a very high concentration of drug, it should have a maximum effect of the drug that proves act. The cell from dying.
然后看看呃，事实上，你可以为某人做很多公寓，可以观察病毒复制，或者在这种情况下看看细胞如何生存，对吗？所以使用细胞系。如果你的化合物可以抑制病毒复制，那么细胞应该是，你知道，如果你有非常高浓度的药物，它应该具有证明有效的药物的最大作用。细胞免于死亡。

Okay? So the y axis is this. Basically, you you you mix the virus, would you infect the cell with the virus and then incubate the cell with a different concentration of drug? And then maybe after some incubation time, you actually measure how many of the cell has died. Okay? If us and then properly, you can imagine the cells, a viability, or the viral, you know, or that you can measure. Yeah. But for some december, I really probably see something like that. So guys, and then you have a very high concentration of job. You you expect have a maximum effect of the drug, right? And on the other on the other hand, we have no, we do not add any drug. We have zero effect. And here, remember, in the enzyme innovation, I introduce you a term called ic 50, right? Inefficient concentration at 50. So in a separate experiment, they use another term called ec 50, okay? Dc 15 minutes, the concentration of the job to achieve50% of its effect, e e sample, in fact, the effective concentration of 50% effectiveness, something like I got the concentration about to achieve 50% of the uh, maximum effect.
好的？所以y轴是这样的。基本上，你混合病毒，你会用病毒感染细胞，然后用不同浓度的药物孵育细胞吗？然后也许经过一段时间的孵化，你实际上可以测量出有多少细胞已经死亡。好的？如果我们正确的话，你可以想象细胞、活力或病毒，你知道，或者你可以测量。是的。但在某个十二月，我真的可能会看到类似的情况。所以伙计们，然后你们的工作就非常集中了。您期望药物发挥最大作用，对吧？另一方面，我们没有，我们不添加任何药物。我们的影响为零。在这里，请记住，在酶创新中，我向您介绍一个术语，称为 ic 50，对吧？浓度为 50 时效率较低。因此，在另一个实验中，他们使用了另一个术语，称为 ec 50，好吗？ DC 15分钟，工作浓度达到50%的效果，ee样品，其实有效浓度50%的效果，像我得到的浓度大约达到50%的呃，最大效果。

So basically, you you plot a graph like this. So this is 100% maximum effect. This is zero effect. And then you put so this should be somewhere in the middle of 50%, in fact. And then you you cut this line and then you look at the concentration of the drug, and this number is the dc 50. Okay? You don't make myself there. Okay, so now we have so we need to distinguish which much of a bridge when we talk about, I say, 50 people refer to the enzymatic effect. I said, do it on the test two.
基本上，你可以绘制这样的图表。所以这是 100% 的最大效果。这是零效应。然后你输入，事实上，这应该在 50% 的中间。然后你剪掉这条线，然后你看看药物的浓度，这个数字是 dc 50。好吗？你不会让自己在那里。好的，现在我们有了，所以我们需要区分，当我们谈论时，我说，50 个人指的是酶促效应。我说，在测试二上做吧。

Okay, when people look at easy 50 on the cell, oh, uh, actually, the value used to describe very commonly the effect of the drug on on on the more biological setting, in this case, is the cell line uh, uh uh, setting. Okay. So and this paper was published in the 2000 20 one, of course, by isis, scientists. And they uh, describe the story how they discovered the inhibitor for covet 19. So this is the actually a uh, initial structure.
好吧，当人们看到细胞上的 Easy 50 时，哦，呃，实际上，这个值通常用来描述药物对生物环境的影响，在这种情况下，是细胞系呃，呃呃， 环境。好的。所以这篇论文发表在2000年第20期，当然是由ISIS的科学家们发表的。他们呃，描述了他们如何发现 covet 19 抑制剂的故事。所以这实际上是一个呃，初始结构。

Ok. Here they also used another term, which is very similar to ilcic 15 is the uh enzyme inhibition constant ki you can see it as the ic 50, maybe even a better one. But here I would not. Um, uh, going to detail how people measure the the ki but you can see that it's similar to isis 15, lower than beta. Okay. So for example, uh, if you have uh, so for this compound, they first discovered in the uh advisers and laboratory. This is a compound called uh have uh have a have aki values of a suit on to better moral land of water. Okay, you see a lot of drugs in the truck company when they um, um, have a good chance of going into a real job. Typically, you want an innovation at the landlord level.
好的。在这里他们还使用了另一个术语，它与 ilcic 15 非常相似，是呃酶抑制常数 ki 你可以将其视为 ic 50，甚至可能是更好的一个。但在这里我不会。嗯，呃，将详细介绍人们如何测量 ki，但你可以看到它与 isis 15 类似，低于 beta。好的。举例来说，呃，如果你有呃，那么对于这种化合物，他们首先是在呃顾问和实验室中发现的。这是一个叫做呃呃有一个有Aki价值观的复合体，适合更好的道德水之地。好吧，你会在卡车公司看到很多毒品，而他们很有可能进入真正的工作。通常，您希望在房东层面进行创新。

Very, very small landlord means 1 time 10 to-9. Okay, one that one, our 1,000 nano molar equals to one micro molar. Okay, 10,000 microphone, right? It goes to $1 million. $10,000 million equals to one polar. So you see one then normal, right? Is time very, very small amount. So it means that you only need a very small amount to achieve the innovations. Yeah. Okay. And then the for a cell based uh, uh antiviral assay, it is also very good. So and uh 200 and all and more than the achieve 50% of the effect already. So this is good. Okay, this this this look like this, at least on paper, it looks good. Okay, that looks promising. But, remember from from enzyme to sell, then you need to go into a living organism, right? And the model of human. And most of the drug that um, but we could be asked if you want if you go to see a doctor.
非常非常小的房东意味着1次10比9。好吧，一比一，我们的 1,000 纳摩尔等于 1 微摩尔。好吧，10,000 个麦克风，对吧？价值达到 100 万美元。 100亿美元相当于一根极地。所以你看到的就是正常的，对吧？时间是非常非常少的。因此，这意味着您只需要很少的资金即可实现创新。是的。好的。然后，对于基于细胞的抗病毒检测，它也非常好。所以呃 200 以及以上已经达到了 50% 的效果。所以这很好。好吧，这个这个这个这个样子，至少在纸面上看起来不错。好吧，看起来很有希望。但是，记住从酶到销售，然后你需要进入一个活的有机体，对吧？还有人类的模型。大多数药物都可以，但是如果您去看医生，我们可能会被问到是否需要。

Okay, so that's okay. So you have this. Uh, this is a how about I give you an injections? Okay? That's a drug. Or you go to a doctor b okay, i'll i'll give you a job then just take the pills. Which one will be for? It's actually suggestion. Or take a pill, I will take a pill in any day, right? You you you don't find yourselves safer, right? So that's why uh, people look at aaa lot of the the drop down on the market that can sell. Okay, they can sell the drug company that they they they need to sell the drug that that's the job. Uh, that can sell are most of them are all you know that can be taken all of it. Okay? So if the drug can only work, if you do an injection, yes, okay, if you die, but but but if if if you don't take it, you die, maybe you can still get it. But uh um it it it also costs a lot to an issue more expensive ok you need to go to hospitals and gestures and so which means that there's one thing, one one additional product.
好吧，那没关系。所以你有这个。呃，这是我给你打针怎么样？好的？那是一种药物。或者你去看医生，好吧，我会给你一份工作，然后吃药。哪一个将用于？其实就是建议。或者吃药，我随时都会吃药，对吗？你，你，你并没有发现自己更安全，对吧？这就是为什么人们会关注市场上很多可以出售的商品。好吧，他们可以把他们需要的药品卖给制药公司，这就是工作。呃，能卖的大部分都是你知道的，能全部拿走的。好的？所以，如果药物只能起作用，如果你注射，是的，好吧，如果你死了，但是但是如果你不服用它，你就会死，也许你仍然可以得到它。但是，嗯，它也花费了很多钱，更昂贵，你需要去医院和手势，所以这意味着有一件事，一个额外的产品。

So not so, you know, being a drug company is not is no fun. Okay? You have to make sure the drug work in the in the test tube. In the biochemistry, you need to make sure that the drug will work in the cell base, but you need to make sure the drug can be eaten, can be taken orally, and don't get destroyed by your stomach, digestion or whatever.
所以事实并非如此，你知道，作为一家制药公司并不是没有乐趣。好的？您必须确保药物在试管中起作用。在生物化学中，你需要确保药物在细胞基础中发挥作用，但你需要确保药物可以吃，可以口服，并且不会被你的胃、消化或其他什么破坏。

Okay, this and ideally, you will get a salt not excrete or or, you know, go to toilet, right? So this is called bio availability, oral bio facility, which means that how many% compared to a intravenous, if the same drug are injected in your blood stream, and for adjacent drug, you take it orally. What are the efficiency? If you talk about 1.4%, it means. Okay. 1998.6% are lost. Okay? All right. Okay, you only get 1.4%, which means that is it is it useful? No, right? We don't want that. So, so, so it means that the drug design is a very complicated business. Okay, you not only you want the drug to inhibit the enzyme. You know, strongly. And it's not on. That's not enough. You also need the drug to be ideally soluble. Liquid fossil can pass through the membrane, so it can be easier absorbed in the in your test side so that you get inside your body, through projections.
好吧，理想情况下，你会得到不排泄的盐，或者，你知道，去厕所，对吗？所以这就是所谓的生物利用度，口服生物设施，这意味着如果将相同的药物注射到您的血液中，与静脉注射相比，有多少％，而对于相邻的药物，您口服。效率如何？如果你说1.4%，那就意味着。好的。 1998.6%丢失。好的？好的。好吧，你只得到1.4%，也就是说它有用吗？不，对吧？我们不希望这样。所以，所以，所以说明药物设计是一个非常复杂的事情。好吧，你不仅想要药物抑制酶。你知道，强烈。而且它还没有打开。这还不够。您还需要药物具有理想的可溶性。液体化石可以穿过膜，因此它可以更容易地被您的测试侧吸收，以便您通过投影进入体内。

Um. So this is another so called uh, uh, compound. I mean, another, um, criteria is called oral about availability. And if you read the paper, they and and one rule of bio oral bound out availability is whether the more increasing the polar component of your compound. It was actually decreasing the power. Um, uh, oral mile, uh, uh, availability. So what they did is that you change it from this functional world, which, in fact, is stronger, you have a stronger innovations to a nitrile control world.
嗯。所以这是另一个所谓的呃呃复合。我的意思是，另一个，嗯，标准被称为关于可用性的口头标准。如果你读了这篇论文，他们和生物口服约束可用性的一条规则是是否更多地增加你的化合物的极性成分。这实际上是在减少力量。嗯，呃，口头英里，呃，呃，可用性。所以他们所做的就是把它从这个功能世界改变过来，事实上，功能世界更强大，你有更强大的创新，到丁腈控制世界。

Fact is confirmed. Ii used in my research uh, 15 years ago. Um, and and you saw that the data they did measure, although ok the enzyme vision is a lousy enzyme inhibitor, right? Compared to this. One is basically everything is the same, except this is a warhead. Okay. They changed the one to acn group, uh, natural group. Actually, the the innovation get. We can the cell base. Anything easy, 15 can worse. But good news is it has a much increase in oral bio availability, right? So you input one thing to decrease the other, you you you know, you make uh, apart. Another criteria was. But but so this is the link apart. So it's a good ambition. So this guy is a good emission for poor, oral about availability. This one improves the bio of our availability, but the innovation is worse. So then what did they do is to try to uh, do chemical modification, as I said, in the very be before, you go to the clinical trial.
事实已得到证实。我在我的研究中使用过，呃，15年前。嗯，你看到了他们测量的数据，尽管酶视觉是一种糟糕的酶抑制剂，对吗？与此相比。一是基本上一切都是一样的，除了这是一个弹头。好的。他们把那个改成了acn组，呃，自然组。事实上，创新得到了。我们可以建立细胞基地。任何简单的事情，15 可能会更糟。但好消息是它的口服生物利用度大大增加，对吗？所以你输入一件事来减少另一件事，你知道，你让呃，分开。另一个标准是。但这就是分开的链接。所以这是一个很好的野心。所以这个人是一个很好的发射者，可以口头谈论可用性。这提高了我们可用性的生物，但创新更糟。那么他们所做的就是尝试呃，进行化学修饰，正如我所说，在进行临床试验之前。

Okay, you make sure you modify your compound based on your enzymatic assay and sell base as a annual study before you try on human, because now if you go to china, human is very, very expensive.
好吧，在你尝试人体之前，你要确保根据你的酶测定修改你的化合物，并作为年度研究出售基地，因为现在如果你去中国，人类是非常非常昂贵的。

Okay, so what did they do is say, um, okay, they remember the the design is gonna start from warheads and also p one. So this is p one, which is mimicking a good to me. There's not much they did. So what they did is actually they noticed that one drawback about have determined magic is the early version they contain peptide bond. Okay? Peptide bond is present in all countries, right? So you can imagine in your stomach, in a small intestine, there are many, many proteins. Because when we eat means this protein is how was to break the peptide bond of the protein found it means, right? It for what? And then chop them down into peptides and the acid so that we can digest them.
好吧，所以他们所做的就是说，嗯，好吧，他们记得设计将从弹头开始，而且还要从弹头开始。这就是 p one，它对我来说是一种模仿。他们做的并不多。所以他们所做的实际上是他们注意到确定魔法的一个缺点是它们的早期版本含有肽键。好的？肽键存在于所有国家，对吧？所以你可以想象在你的胃里，在小肠里，有很多很多的蛋白质。因为当我们吃的时候就意味着这个蛋白质是怎么被打破的蛋白质的肽键发现的，对吧？是为了什么？然后将它们切成肽和酸，以便我们可以消化它们。

Again, folks have died of magic because you you remember, this is a proactive group, this is the appetite. This is the peptide, this is a peptide and this is the warhead. So the fact that it has a peptide, it's a it's a peptide in causing peptide bond and peptide bond can be digested. This inhibitor can be digested by approaches right inside your god and small intestine. So it's not good. So what do they do? They make modifications? Okay. The main modifications into, okay, for example, they so you've got these two peptide bonds as there's a new thing at the p two positions. So, uh, what they do is is that they doing and you see they do a ring structure, which is a kind of like this. Okay? And then in this case, you, in this case, because the losing is naturally occurring, right? Enzymes, human enzymes in the digestive system can recognize a leucine. So if you change it to something that doesn't look like, you see, but also break this. Uh, and you know, if if you introduce this uh uh brain structure, it will also destroy this uh uh amide bond and make it less likely to be digested by okay, by your digest events.
再说一次，人们死于魔法，因为你记得，这是一个积极主动的群体，这就是胃口。这是肽，这是肽，这是弹头。所以事实上它有一个肽，它是一个肽，它能产生肽键，并且肽键可以被消化。这种抑制剂可以通过肠道和小肠内的途径被消化。所以这不太好。那么他们做什么呢？他们进行修改吗？好的。主要的修改是，好吧，例如，它们这样你就得到了这两个肽键，因为在 p 两个位置有一个新的东西。所以，呃，他们所做的是他们所做的，你看到他们做了一个环形结构，这是一种类似的结构。好的？那么在这种情况下，你在这种情况下，因为失败是自然发生的，对吗？酶，人体消化系统中的酶可以识别亮氨酸。因此，如果你将其更改为看起来不像的东西，你会看到，但也会打破这一点。呃，你知道，如果你引入这个呃呃大脑结构，它也会破坏这个呃呃酰胺键并使其不太可能被你的消化事件消化。

Okay? So, and this is something that they made. Yeah. Remember, this is this is cycling. A new sea method, a chemical control group that looks alike, three dimensional way to a using into. Okay, and then the what they going on is to modify their remember as a protective role. So this is now they modify. So for for this company of p one, p two and remember for the design of the practical magic inhibitor, you also have a protective growth. So this is the initial compound they have. And what do they do is that they they modified us to introduce a residues with that food. Um, that would try to to interact with the that would look like ap four rescues. Ok that would uh interact with the subside free, although it's not much to to interact with and also modify this world, okay, into this compound so that he can fit okay, dog into the subside for now this compound after interacting with. So this is the crystal structure, the structure of the of the of the final compound they marketed. They show that they can interact with the uh, this guy can interact with the subset one, subset two, subside three, and subside four, and then this compound after optimization.
好的？所以，这是他们做的。是的。请记住，这就是骑自行车。一种新的海洋方法，一种看起来相似的化学对照组，以三维的方式使用。好吧，然后他们要做的就是修改他们的记忆作为保护角色。所以这是他们现在修改的。所以对于这个公司的p一，p二，记住实用魔法抑制剂的设计，你也有一个保护性的成长。这就是他们最初的化合物。他们所做的就是他们对我们进行了改造，在该食物中引入了残留物。嗯，这会尝试与看起来像四号救援的人互动。好吧，那会呃自由地与下沉互动，尽管与这个世界互动并修改这个世界并没有太多，好吧，进入这个化合物，这样他就可以在与交互后暂时适应这个化合物。这就是晶体结构，他们销售的最终化合物的结构。他们表明他们可以与呃，这家伙可以与子集一，子集二，沉降三和沉降四相互作用，然后是优化后的这个化合物。

Okay, remember, initially, you have a file, uh, availability of 1.4%. Wow, this one is actually have a lot of improvement. So this guy has a oral amount of an opinion of 50%. That's good, right? Which means that, for example, if you you compared to 100%, is the same drug injected, intervene. Is that okay? This? I directed the book. So oral absorption achieved 15% of project in direct injection is um, is very, very good. Okay. So you have an oral um, file a very deal 50%. And then the inhibition still a little bit weaker than the original compound, but still is still get inhibited as 3 nano molar. Because it doesn't really matter because it's the final concentration that reach your body is important, right? So imagine the power of an ability. You even if the if this compound get inhabit, the enzyme, very importantly, in the test two. But the problem is you cannot get a salt. It's still zero.
好吧，记住，最初，你有一个文件，呃，可用性为 1.4%。哇，这实际上有很多改进。所以这家伙的口头意见量是50%。那很好，对吧？这意味着，例如，如果你与100％相比，注射的是相同的药物，则进行干预。可以吗？这？我执导了这本书。所以口服吸收达到了直接注射项目的15%,嗯,非常非常好。好的。所以你有一个口头嗯，提交一个非常交易 50%。然后抑制仍然比原始化合物弱一点，但仍然被抑制为3纳米摩尔。因为这并不重要，重要的是到达你身体的最终浓度，对吗？所以想象一下一种能力的力量。即使这种化合物存在，酶也非常重要，在测试二中。但问题是你买不到盐。仍然是零。

So, um, the subway easy 50 is even if you compare it, because this one has is more hydrophobic, probably you can easily pass through the same way to get inside the cell. Although they are inside, inside inhibition is sent to weaker, but if you use a cell base is actually have an improvement compared to the original compound is a better cell base, uh, easy, 50, easy, 50 as a better, much, much better of oral power availability city. And this is actually the compound, uh, the mattress uh, that they marketed in their threshold castle.
所以，嗯，地铁easy 50是即使你比较它，因为这个有更多的疏水性，可能你可以很容易地通过同样的方式进入细胞内部。虽然它们在里面，里面的抑制是比较弱的，但是如果你用细胞碱的话其实是有进步的，比原来的化合物是更好的细胞碱，呃，容易，50，容易，50更好，很多，口服电力可用性城市要好得多。这实际上是他们在门槛城堡中销售的复合物，呃，床垫。

Uh. Okay. So. Okay, then before that, okay, then you also need to. But the drought that they use for uh for treating uh coronavirus is is actually the parcel of it. Um, the the next thing they need to to look into is uh, how fast the drug is excluded? How many to go to see the uh uh the doctor? Okay? Sometime, okay, the doctor will. Okay, ii give you this drug, okay? Uh, some drugs you need to only take it once per day, right? Some drug you need, you need to take it. And two per day, some are three per day, some are four per day. So actually, how do the doctor know? Actually, this is so called the particle genetics. We need to do it as well. So for example, this is the experiment. They did it on using animal. Okay, I think it's easier. Animal 17. Yeah. Ok. Probably no. This is already a um, a human study, but you could use a uh, so so this is the idea.
呃。好的。所以。好吧，那么在那之前，好吧，那么你也需要。但他们用来治疗呃冠状病毒的干旱实际上是其中的一部分。嗯，他们接下来需要研究的是，药物被排除的速度有多快？有多少人去看呃呃医生？好的？有时候，好吧，医生会的。好吧，我给你这个药，好吗？呃，有些药物每天只需服用一次，对吧？有些药你需要，你需要服用。而且每天两个，有的每天三个，有的每天四个。那么实际上，医生怎么知道呢？实际上，这就是所谓的粒子遗传学。我们也需要这样做。例如，这就是实验。他们用动物做到了这一点。好吧，我认为这更容易。动物 17. 是的。好的。可能不会。这已经是一项人类研究，但你可以使用呃，所以这就是这个想法。

So, okay, so this is the drug. Remember, this is the inhibitor called the matter from okay, they tried to do the experiment, okay? And then the they measure as the either the animal or you can use the animal study or you can do it on the patients. And and basically what you did, what they did is, okay. Um, you and then you measure the and then after the animal or the human subject taking the drug, and then you take blood sample from the animal or from the from the subject uh as a function of time. And then you measure the concentration of the of the drug in the blood, okay, as a function of time. So obviously, for every time you take the drug, your your body will matter, will will metabolize a drug and get it excluded and breaking it down, right? So you can imagine the concentration of the drug in your blood would always go down. Okay. So so and then and then you can use the easy tips, okay? Then and then typically the user, uh, uh, ii say now they use another uh, another uh, concept called easy 19. If you understand what is the easy 15, you can understand what is the easy 5, 5090. It means that the concentration of the job that can achieve 90% of maximum effect.
所以，好吧，这就是药物。记住，这是抑制剂，他们试图做这个实验，好吗？然后他们测量动物，或者你可以使用动物研究，或者你可以对病人进行测量。基本上你所做的、他们所做的都是好的。嗯，然后你测量，然后在动物或人类受试者服用药物后，然后你从动物或受试者身上采集血液样本作为时间的函数。然后你测量血液中药物的浓度，好吧，作为时间的函数。很明显，每次您服用药物时，您的身体都会很重要，会代谢药物并将其排除并分解，对吧？所以你可以想象你血液中的药物浓度总是会下降。好的。如此如此，然后你就可以使用简单的技巧了，好吗？然后通常用户，呃，呃，ii 说现在他们使用另一个呃，另一个呃，称为 easy 19 的概念。如果你理解什么是 easy 15，你就可以理解什么是 easy 5，5090。这意味着能达到最大效果90%的工作浓度。

Well, we that that's a good two things, so which means that So initially, after we take the drug, the concentration of the drug in your blood is higher, then the concentration ec 59, so which means that it is effective, right? But after maybe, so this is 6 hour, maybe after 2 hour, maybe 3 hour, max, right? After 3 hour, the concentration of the drug below now going down below, you see, 50, which means that the effective concentration of just going down, right? Lower than 90, and maybe lower and lower. Okay? Typically you can use the ec 90 as a guideline to see how long the drug will stay in your body to remain effective? So obviously, this is actually not ideal, right? If you have a drop that only last for, I don't know, maximum 3 hours, maybe 2 hours, okay, let's say 3 hours. That if if I market this drug, um, the doctor would need to describe how many how many times you did. Is it the drug per day? So you are safe in times. It's not, right. Do you think the drug will sell? Right.
嗯，我们认为这是一件好事，所以这意味着，所以最初，我们服用药物后，您血液中药物的浓度较高，然后浓度为 ec 59，所以这意味着它是有效的，对吧？但也许之后，所以这是 6 小时，也许 2 小时后，也许 3 小时，最多，对吗？ 3小时后，下面的药物浓度现在下降到50以下，这意味着有效浓度刚刚下降，对吧？低于90，甚至可能更低。好的？通常，您可以使用 ec 90 作为指导来查看药物将在您体内保留多长时间以保持有效？显然，这实际上并不理想，对吧？如果你有一滴只能持续，我不知道，最多 3 小时，也许 2 小时，好吧，假设 3 小时。如果我推销这种药物，嗯，医生需要描述你做了多少次。是每天吃药吗？所以你有时是安全的。不是这样的，对吧。你觉得这个药会卖吗？正确的。

So so it is still usable, but not ideal. Am I right? Right? You know, probably you don't want to take a drug that that is taken every 2 to 3 hours, right? Even there's no margin of error idea. Okay? So in this case, so we need to find they what what pfizer do was. Okay, this scratch ahead. How do they improve? They're half life. Okay? How how can I make the the drugs stay longer inside human body? So they they and with another trade, which is, uh, in fact, the parcel of it as a as a drug is not a single compound. They have 2 active°. The second uh active ingredient is not a is, in fact, a uh compound call retard about. Okay, retirement is an inhibitor of an enzyme called cyclone p four50, uh, uh, three, a four subtype. So this is an inside inside a liver that would be mainly responsible for breaking down drugs.
所以它仍然可以使用，但并不理想。我说得对吗？正确的？您知道，您可能不想服用每 2 至 3 小时服用一次的药物，对吧？甚至没有任何误差幅度的想法。好的？所以在这种情况下，我们需要找到他们辉瑞做了什么。好吧，这就是前面的划痕。他们如何改进？他们是半条命。好的？怎样才能让药物在人体内停留的时间更长呢？所以他们和另一项交易，呃，事实上，它作为药物的一部分不是单一的化合物。他们有 2 个活跃°。第二种活性成分实际上不是一种称为延迟的化合物。好吧，退休是一种叫做旋风p four50的酶的抑制剂，呃，呃，三，四亚型。所以这是肝脏内部主要负责分解药物的内部。

Okay? So the idea is if you take the take the uh, inhibitor at the same time when they uh, retirement of the the inhibitor for the p 450. Remember, if you if if you if you add this, when thomas are you, you inhibit the enzyme that break down the truck? So that makes sense. So if you give him, if if you intake the drug, both the main proteins independent as well as the return of, you can increase, right? The plasma concentration and allow your drug to stay longer. And so this is the uh, medium plasma concentration. Okay, if the patients take uh, take the drug with this limiter for the uh, uh, we call it 6384 of the then you see the concentration that about the ec 19 will be stay longer, maybe something like uh, 18 hours, right? So that's why this drought, what this was prescribed as take 2 times a day, right? That makes sense, right? So if you talk about 12, it's okay, then you put another shoot. Okay? So it means that at all time, if you if if so this drug is actually yeah, this based on this data, now the doctor of the drug company okay, can recommend the doctor to recommend you to take the pill, take it 2 times for that, because uh, we talk about 12 hours of you know, of the concentration about the easy uniting.
好的？所以这个想法是，如果你在他们呃，抑制剂退休的同时采取呃，抑制剂p 450。记住，如果你如果如果你添加这个，当托马斯是你时，你抑制分解卡车的酶？所以这是有道理的。所以如果你给他，如果你摄入药物，无论是主要蛋白质的独立还是回归，你都可以增加，对吗？血浆浓度并使您的药物停留时间更长。这就是呃，中等血浆浓度。好的，如果患者服用呃，服用带有这个限制器的药物，呃，呃，我们称之为 6384，那么你会看到大约 ec 19 的浓度会停留更长的时间，也许像呃，18 小时，对吧？这就是为什么会出现干旱，规定每天服用两次，对吗？这有道理，对吧？所以如果你说12，没关系，然后你再拍一次。好的？所以这意味着在任何时候，如果你如果是的话这个药实际上是的，这个根据这个数据，现在制药公司的医生好吧，可以推荐医生推荐你吃药，吃2次为此，因为呃，我们谈论了 12 个小时，你知道，专注于轻松团结。

So after this course, you should never you should be always remember when when you see a doctor remember to take your pill, okay, on time, okay, everything is very scientific.
所以学完这个课程之后，你永远不要记住，当你看医生的时候记得吃药，好吧，按时，好吧，一切都很科学。

Okay, so so, yeah, so, um, and so this is the and and so this is after they this is all signs, okay? They after they call this all this information, then they decided to go to chemical drop. And the clinical trial, the result of the chemical trial has been published in the new england journal, uh medicine in 2022. And uh, this is a very long paper. Okay? So ii just summarize the most important result here. Okay, so the idea is, okay, so typically, you you divide the the the subject into 2 rows, okay? One group with the placebo basically. Okay, something that is no active ingredient that another with the uh, uh, the venture thought is this is the main process that this is a viral inhibitor. And then the 300 milligram. And that this is the inhibitor for the enzyme to break down. The the drug. Okay? And then again, this is the 12 hour, okay? That makes sense. And for 5 days, and then the they also divided the uh, basically divide the patients the subject into 4 groups. One point is uh, with the real drug, the other okay, the drug drug treatment world, ok and then they further divided instruction model into 21 is entered for the patients who uh uh, within 3 days of symptom onset.
好吧，所以，是的，所以，嗯，所以这是，所以这是在他们之后，这是所有的迹象，好吗？他们在称其为所有这些信息后，决定进行化学滴落。还有临床试验，化学试验的结果已经发表在2022年的新英格兰杂志呃医学上。而且呃这是一篇很长的论文。好的？所以我在这里总结一下最重要的结果。好的，所以想法是，好的，通常，您将主题分为两行，好吗？一组基本上使用安慰剂。好吧，这是没有活性成分的东西，另一个呃，呃，冒险者认为这是病毒抑制剂的主要过程。然后是300毫克。这是酶分解的抑制剂。该药物。好的？再说一次，这是 12 小时，好吗？这是有道理的。持续5天，然后他们也把呃，基本上把病人分为4组。一点是嗯,用真药,另外还好,药物治疗世界,好然后他们又把指导模型分成了21个,输入给呃呃,症状出现3天之内的病人。

The other is within 5 days of symptom concept.
另一种是出现症状后 5 天内。

Okay? Because you can basically want to test, because somebody will argue that if the symptom has already onset for 5 days, uh, it's no use, right? So they tried this uh uh to to experimental setting.
好的？因为你基本上可以想要测试，因为有人会争辩说，如果症状已经出现了 5 天，呃，那就没有用了，对吧？所以他们尝试了这个呃呃实验设置。

Okay, so so this is the treatment group. This is the control placebo group. So if you, for example, I just look at this number for the for the treatment group. Okay, altogether. Okay. They treated 1,000 c in the chemical trial phase. Phase number three, you you talk about thousands of patients to get good statistics, whether your job is working or not.
好的，这就是治疗组。这是对照组安慰剂组。例如，如果你，我只看治疗组的这个数字。好吧，全部。好的。他们在化学试验阶段处理了 1,000 摄氏度。第三阶段，无论你的工作是否有效，你都会谈论数千名患者以获得良好的统计数据。

Okay. So for this one, if you take the job uh, within 5 days of symptom onset, only eight of them. Okay, we eventually go to need to go to hospital. Thank you. But on the other hand, if uh, this is not actually no good, okay. So, yeah, so for the placebo group control group with no active ingredient, again, the total number of patients also similar 1,046. Well, this is no good troll from that side. Okay, 66 of them has to, you know, that symptom get worse. And then eventually they need to go to the hospital. So, yeah, so that's why this this truck has been approved, especially now in in hong kong. Um. Uh, i'm not sure in whatever another place, okay? Uh, if you're 16 years old or old, okay. Then if your doctor thinks you do not, uh, uh, but this one has a subsider, because it would actually inhibit uh, the the drunk that the enzyme that put down other drugs. So uh this this uh uh parcel of it would not be uh usable for those who already uh have a chronic disease, also have uh eating other drugs that would be not suitable, because we also uh basically it uh screw it it mess around with these uh found group united.
好的。所以对于这个，如果你接受这份工作，呃，在症状出现后 5 天内，只有 8 个。好吧，我们最终还是需要去医院。谢谢。但另一方面，如果呃，这实际上并不是没有好处，好吧。所以，是的，对于不含活性成分的安慰剂对照组，患者总数也相似，为 1,046 人。好吧，从那方面来看，这不是一个好巨魔。好吧，其中 66 个，你知道，症状会变得更糟。最终他们需要去医院。所以，是的，这就是为什么这辆卡车获得批准，特别是现在在香港。嗯。呃，我不确定在其他地方，好吗？呃，如果你是16岁或以上，好吧。那么如果你的医生认为你没有，呃，呃，但是这个有一个消退剂，因为它实际上会抑制呃，放下其他药物的酶的醉酒。所以呃这个呃呃这个包裹对于那些已经呃呃患有慢性疾病，也呃呃吃其他不适合的药物的人来说是不可用的，因为我们也呃基本上它呃搞砸了它弄乱了这些呃发现团队团结了。

But otherwise, I think the data speak for themselves, right? You reduce your chance of dying and reduce the chance of going to hospital. Basically, it's slow down or decrease the security of the symptoms. Okay, and then this combination of the drugs are now marketed as so called axle it. Okay, buy some to treat 2019. So, last slide. So, now that's that's a good story. I use the packs of it as a story to give you some, I think today's lecture I give you from very beginning on the mechanism of the the season, introduction of the disease of the virus going to some journal view on drug design and also using tax profit as an example to see.
但除此之外，我认为数据本身就说明了一切，对吗？您可以减少死亡的机会并减少去医院的机会。基本上，它会减缓或降低症状的安全性。好的，然后这种药物组合现在作为所谓的轴它进行销售。好的，买一些来款待 2019 年。所以，最后一张幻灯片。所以，现在这就是一个好故事。我用它的包作为一个故事给你一些，我想今天的讲座我从一开始就给你讲了季节的机制，介绍了病毒的疾病，以及一些关于药物设计的期刊观点，也使用了以税收利润为例看。

At least I gave you a successful example, but many of them are not successful to remember that. Okay, only 7.9%. For those from that get into the chemical trial one can eventually got marketed. Um. But but what's more? Okay, what's futures? Ok so now this retailer could introduce side effect as can interfere with the trump metabolism by by this enzyme. So with it, i'm not sure people would still spend money on this coverage is not so long. Um. Yeah, I suspected no, but um, yeah, um, but but again, scientifically speaking, will it be further improve the path of it? So then we can carry off as a retirement. So that to provide a better drug that can because the passover cannot be given described to dose patients whom the disease with other. We're taking other drugs that would have complications.
至少我给了你一个成功的例子，但他们中的很多人都没有成功地记住这一点。好吧，只有7.9%。对于那些参与化学试验的人来说，最终可以将其推向市场。嗯。但是，还有什么？好吧，什么是期货？好吧，现在这家零售商可能会引入副作用，因为这种酶会干扰特朗普的新陈代谢。因此，我不确定人们是否还会花钱购买这个不那么长的保险。嗯。是的，我怀疑不是，但是嗯，是的，嗯，但是，从科学上来说，它会进一步改善它的路径吗？这样我们就可以退休了。因此，提供一种更好的药物，可以因为逾越节不能给予患有其他疾病的患者服用。我们正在服用其他会引起并发症的药物。

And another thing is coffee has now caused three epidemic. Sars in 2003. Mars, whether he's uh respiratory syndrome in 2012 and coffin, right? Just a few years ago. Were they coming in? What do you think? Okay, of course on a good intention, we wish the coffin or whatever is wearing will not come again. But you look at the history, i'm a little bit less optimistic about that. If it hit it once, you can say, okay, never strike again. It hits two time. If you still think it doesnt, it will not come again. Now he hit it 3 times. I'm not sure. Okay. So given that, I don't know, okay? So, but but the good news is, I think the proteins inhibitor is still the way to go. Remember. The proteins inhibitor that we have been developing, they are tend to have a property of broad spectrum. Right? The inhibitor ii work on 15 years ago, I tried on alpha, beta, gamma, they all individual.
还有一件事是咖啡现在已经引起了三场流行病。 2003年的非典。火星，他是否是2012年呃呼吸综合症和棺材，对吧？就在几年前。他们进来了吗？你怎么认为？好吧，当然是出于好意，我们希望棺材或任何穿着的东西不会再出现。但你看看历史，我对此就不那么乐观了。如果它击中了一次，你可以说，好吧，再也不会击中了。打了两次。如果你仍然认为没有，那么它就不会再来了。现在他击中了3次。我不知道。好的。鉴于此，我不知道，好吗？所以，但好消息是，我认为蛋白质抑制剂仍然是可行的方法。记住。我们一直在开发的蛋白质抑制剂，它们往往具有广谱特性。正确的？抑制剂ii在15年前起作用，我尝试过α、β、γ，它们都是单独的。

So I would say, of course, the vaccination that expired on my machine would be much quicker. I can tell you because uh the surface uh, professor is good. Don't don't get me wrong. Resonance is good for, even if you the rest, as I say, it, even it doesn't prevent you from getting a the disease. But the data is still convincingly showing that it would decrease your chance of dying.
所以我想说，当然，在我的机器上过期的疫苗会快得多。我可以告诉你，因为呃表面上呃教授很好。别误会我的意思。共振是有好处的，即使你其余的，正如我所说，它，即使它不能阻止你患上这种疾病。但数据仍然令人信服地表明，它会降低你的死亡几率。

Okay? Okay, you still get a disease, but you typically have lower sense symptom. You know, the symptoms are less severe, and you don't go to hospital as uh probability the same for possible. So I don't know, I think the, but cholera viral disease may come again. Okay, if it hit up 3 times over the last 20 years, byebye. It could hit us. I don't know. In the coming years. Okay, good, okay. Of course I don't want it to, but but yeah. But I but still the proteins in a bit that they are developed so far, too well. Since the substrate sequence of the main proteins are very difficult, so I suspected that inhibited elevens could be used it to fight future called valuable effect. So that will be a 9 five years ago, in 2019, we have nothing.
好的？好吧，你仍然会生病，但你通常会出现低感觉症状。你知道，症状不太严重，而且你也不会去医院，因为可能性是一样的。所以我不知道，但我认为霍乱病毒病可能会再次出现。好吧，如果它在过去 20 年里上涨了 3 次，再见。它可能会袭击我们。我不知道。未来几年。好吧，好吧，好吧。我当然不希望这样，但是，是的。但我仍然对蛋白质有一点了解，到目前为止它们已经开发得很好了。由于主要蛋白质的底物序列非常困难，所以我怀疑抑制十一烯可以用它来对抗未来的所谓有价值的效果。所以那将是五年前的 9，2019 年，我们什么都没有。

Now we get something. Okay, we have some messing with our investing. We have this approaches in the bitter. So I still believe that we are better protected. Okay, if if the camaraderie are going award to no cost another academy in the coming years. So the suggested reading. Oh, this, I said, is the last slide, but this is the last last last slide, okay? So this is suggested reading. I find it a quite good read. Okay, um. They they just. Yeah, this page is a review paper. Um, you can sort of you should give you are in syria today, um, network or in vpn you should be able to assess achk library, um, gives you aa if you're a safety student, you should be able to download this paper free of charge. Um, yeah, if you have time, you can speaking. And I think it's a good meeting. Good. That's definitely the last slide. Good timing. That's where we are.
现在我们得到一些东西。好吧，我们的投资有些混乱。我们在痛苦中采取了这种方法。所以我仍然相信我们受到了更好的保护。好吧，如果友情在未来几年内能够免费授予另一所学院的话。所以建议阅读。哦，我说这是最后一张幻灯片，但这是最后一张最后一张幻灯片，好吗？所以这是建议阅​​读的内容。我觉得这是一本很好读的书。好吧，嗯。他们他们只是。是的，这一页是一篇评论论文。嗯，你可以给你一个今天在叙利亚的信息，嗯，网络或者VPN，你应该能够评估achk库，嗯，给你aa，如果你是安全学生，你应该能够下载这个纸张免费。嗯，是的，如果你有时间的话，你可以说。我认为这是一次很好的会议。好的。这绝对是最后一张幻灯片。时机很好。这就是我们现在的处境。