瑞德西韦抑制RdRP分子生物学原理

COVID-19 Medication Treatment Trials, Global Testing Remains Limited (lecture 33)

Welcome to another MedCram covid-19 update. This is for Monday, the 9th of March. Here in orange, mainland China’s cases are leveling off. The total recovered is increasing mainly because of the numbers generated from mainland China, but at other locations, we are starting to see things pick up as well.

欢迎来到MedCram covid-19的另一个更新。这是3月9日,星期一。在这里,中国大陆的病例数量趋于稳定。康复总量增加的主要原因是来自中国大陆的康复数量,但是在其他地区,我们也开始看到情况有所好转。

If we look at the country-specific statistics, we can see of course China at the top, but interestingly if we look at South Korea and Italy, these are two very comparable countries here in terms of total cases. If you look at their populations, total cases per 1 million, they’re also similar: 145 versus 122. We know however that South Korea has done aggressive testing. Close to 200,000 people have been tested in that country.

如果我们查看特定国家/地区的统计信息,我们当然可以在顶部看到中国,但是有趣的是,如果我们查看韩国和意大利,就总病例而言,这是两个非常可比的国家。如果看一下他们的人口,即每百万的总病例数,它们也相似:145对122。但是我们知道,韩国已经进行了积极的测试。在那个国家已经有将近20万人接受了测试。

So I believe what you’re seeing here, with close to 200,000 people being tested, this number is probably pretty close to people who are actually infected in that country. Whereas in Italy, this may represent more of a tip of the iceberg.

因此,我相信您在这里所看到的,大约有200,000人正在接受测试,这个数字可能与该国实际感染的人非常接近。在意大利,这可能只是冰山一角。

As a result of that, we can see that potentially explain here is the total deaths. If the virus is having the same effect in both countries, and at the healthcare delivery systems in both countries are similar, you would expect total deaths here to be similar. Serious and critical, that’s another category where there is a serious difference (between South Korea and Italy).

结果,我们可以看到,这可能是造成死亡总数的原因。如果该病毒在两个国家/地区具有相同的作用,并且两个国家/地区的医疗保健提供系统相似,那么您预计此处的总死亡人数将相似。严重病例及危险病例,这是另一个(韩国和意大利)区别明显的类别。

The big news in Italy is that they are taking what they call exceptional measures to contain about 16 million Italians living in 14 provinces in the north of the country, as well as restrictive measures covering the whole of the country. You can see here in those areas, we have travel being restricted; gatherings, all schools and universities, are closed; all museums and places of culture will be closed; all religious festivals and events are suspended. You can see cinemas, pubs, theaters, etc. etc. Any places where people congregate are being severely restricted or closed.

意大利的一大新闻是,他们正在采取所谓的特殊措施,以遏制生活在该国北部14个省中的约1600万意大利人,并采取覆盖整个国家的限制性措施。您可以在这些地区看到我们的旅行受到限制;所有学校和大学的聚会都关闭了;所有博物馆和文化场所将关闭;所有宗教节日和活动都被暂停。您可以看到电影院,酒吧,剧院等。在人们聚集的任何地方都受到严格限制或关闭。

In the United States with more testing, we’re going to see an explosion here, I believe, of people that are going to be positive, and you can see all of those here listed at Worldominator.

我相信,在美国,经过更多测试后,我们将看到阳性病例将会爆炸,您可以在Worldominator上看到所有列出的人。

Okay, we’ve received a lot of questions about covid-19 treatment possibilities that may be on the horizon. Medications like remdesivir that we discussed in our Video Update 11 that have shown promising results in a test tube and are in clinical trials with humans as we speak.

好的,我们已经收到了许多有关即将出现的covid-19治疗可能性的问题。我们在视频更新11中讨论过的类似remdesivir的药物在试管中显示出令人鼓舞的结果,并且正在与我们交谈的人体临床试验中。

Here’s a paper that was published on February 24 that gives more information about how remdesivir actually works. We will put a link in the description below. This medication had gone through phase one trial already, had gone through phase two trials where they looked at safety again except in a larger population.

这是2月24日发布的一篇论文,提供了有关remdesivir实际工作原理的更多信息。我们将在下面的描述中放置一个链接。这种药物已经通过了第一阶段的试验,已经通过了第二阶段的试验,除了人口更多以外,他们再次考虑了安全性。

But when they did the phase 3 trials on Ebola, it did not work. So even though you can get something that works in vitro, it doesn’t always mean it’s going to work in vivo. You have to go through those phase 3 trials before the FDA will give it a label.

但是,当他们对埃博拉病毒进行3期试验时,它没有效果。因此,即使您可以获得体外可以使用的产品,也并不总是意味着它将在体内使用。您必须经过FDA的标签才能进行第3期试验。

Well, the fortunate thing about this medication is it past phase 1, phase 2, so we know it’s a medication that’s relatively safe, and it’s sitting on the shelf for a job to do.

好吧,这种药物的幸运之处在于它已经超过了第1阶段,第2阶段,因此我们知道这是一种相对安全的药物,而且它摆在架子上可以做。

Now enter this covid-19 situation here at the beginning of 2020, it’s being put to work directly into a phase 3 trial. So the nice thing here is that it didn’t have to go through Phase 1 and 2 because it already did that.

现在,在2020年初在这里进入covid-19的局面,并将其直接投入到第3阶段试验中。因此,这里的好处是它不必经过第一阶段和第二阶段,因为它已经做到了。

Before we continue to talk about remdesivir, we need to follow up on what I illustrated in our last video, Update 32, about how the SARS-cov-2 virus, which causes covid-19, actually hijacks our cells. Something called RNA-dependent-RNA-polymerase, or RdRP for short, is essential for the replication of RNA viruses. Please go back and watch this video so you have context.

在继续谈论瑞德西韦之前,我们需要跟进我在上一个视频Update 32中说明的内容,即导致covid-19的SARS-cov-2病毒实际上如何劫持我们的细胞。 RNA依赖性RNA聚合酶(简称RdRP)对于RNA病毒的复制至关重要。请返回并观看此视频,以便您了解具体情况。

So let’s zoom in and look closely at the function of RdRP because that’s going to tell you why remdesivir may or may not work. So here’s our RNA-dependent-RNA-polymerase, and here’s our viral RNA. You can see the nucleotides here AUGCGCU.

因此,让我们放大并仔细查看RdRP的功能,因为这将告诉您为什么瑞德西韦可能有效或无效。这是我们的RNA依赖性RNA聚合酶,这是我们的病毒RNA。您可以在此处AUGCGCU看到核苷酸。

What RNA dependent RNA polymerase is whenever they see an A on the first strand, it will create a strand that has a U. Whenever they see a U, it will put in an A. Whenever they see a G, it will put in a C. Whenever it sees a C, it will put in a G, and so forth and so forth. The way that this works is it always creates RNA from the five prime end to the three prime end, which means that it’s reading the template RNA from the 3 prime end to the 5 prime end.

什么是RNA依赖性RNA聚合酶,只要他们在第一条链上看到A,就会创建一条具有U的链。每当他们看到U时,就会放入A。每当他们看到G时,就会放入A。 C.每当看到C时,它将放入G中,依此类推。这种方法的工作方式是始终从五个主要末端到三个主要末端创建RNA,这意味着它正在从三个主要末端到5个主要末端读取模板RNA。

So here it’s coming up to the next nucleotide, and there are these things floating around, and they have three phosphates on them. All of them have three phosphates. And so the way that this is abbreviated as they’re floating around in the cytosol.

因此,这里是下一个核苷酸,这些东西四处漂浮,上面有三个磷酸酯。他们都有三种磷酸盐。因此,由于它们在细胞质中漂浮,因此将其缩写。

For instance, if this is an A, this would be known as adenosine triphosphate, or ATP. This one here would be known as UTP. What happens is as these nucleotides, which are just floating around in solution, there’s a spot that opens up. Because this is a G, one of them that has a C on it, and three phosphates, will nicely bind in here, and it will form C, and it will continue to go on.

例如,如果这是A,则称为三磷酸腺苷或ATP。这在这里被称为UTP。发生的事情是这些核苷酸在溶液中四处漂浮,有一个开放的点。因为这是一个G,所以其中一个上面带有C的磷酸酯和三个磷酸酯会很好地结合在此处,并形成C,并且它将继续下去。

I’m just going to erase some of this here so that we can see it a little bit more clearly. The thing that’s really interesting about this is when it comes to the time when there is a U that opens up, ATP should normally go in there. Remdesivir, as will abbreviate RDV, with a 3-phosphate on the end of it, actually binds into this U state better than the A, and so it will go in there instead.

我将在此处删除其中一些内容,以便我们可以更清楚地看到它。真正有趣的是,当有一个U打开时,ATP通常应该进入该位置。 瑞德西韦缩写为RDV,其末端带有3-磷酸酯,实际上它比A更好地结合到U状态,因此它将进入那里。

Here’s the nice thing about RDV in the situation. As soon as RDV binds, as this RNA molecules being copied, about three or four nucleotides down the line, it causes the RNA dependent RNA polymerase to stop. It arrests RNA dependent RNA polymerase.

在这种情况下,这是有关RDV的好处。 RDV结合后,随着该RNA分子被复制,立即下降大约3或4个核苷酸,这将导致RNA依赖性RNA聚合酶停止。它阻止RNA依赖性RNA聚合酶。

If you scroll down to the bottom, you can see that remdesivir triphosphate is very similar to adenosine triphosphate. Look at the structure. It’s going to fit very well inside of that spot as the RNA dependent RNA polymerase is going by. But if you have a concentration of RDV-TP in the cytosol, it will suck one of those in and arrest elongation. If you arrest elongation of the RNA, you can’t make viruses, and you stop the infection and its tracks. So you can see why this medication has a lot of promise. But again we have to do the randomized placebo-controlled trials, and those are underway as we speak.

如果向下滚动到底部,您会看到瑞姆西韦三磷酸与三磷酸腺苷非常相似。看一下结构。随着RNA依赖性RNA聚合酶的通过,它非常适合该斑点。但是,如果您在浆液中含有RDV-TP浓度,它将吸收其中的一种并阻止伸长。如果阻止RNA的延长,就无法制造病毒,并停止感染及其轨迹。因此,您可以了解为什么这种药物有很多前途。但同样,我们必须进行随机安慰剂对照试验,而这些在我们做这场讲座时仍在进行中。

Thanks for joining us.

感谢您加入我们。

MedCramChina

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