Thread by @jenheemstra

At this point, you’ve probably heard a ton about chloroquine and hydroxychloroquine and how they may be effective in treating COVID-19. I wanted to tell you about a different molecule that’s getting less attention but may have good potential – Remdesivir.

I’m not an epidemiologist, so I can’t comment on the clinical trials any more than your average citizen scientist. However, I am a chemist and so I can tell you about the super cool science behind how Remdesivir functions to inhibit viral replication.

Remdesivir is in a class of molecules called “nucleotide analogues.” When a virus infects a cell, it releases its genome – either DNA or RNA, depending on the virus. It then goes to work making as many copies of that genome as it can so that it can multiply and spread.

These copies are made by enzymes called polymerases. In the case of coronavirus, the genome is made of RNA, and so the polymerase is an RNA-dependent RNA polymerase – it takes the RNA template and makes RNA copies of that.

If you’re like me, when you’re trying to make as many copies of something as possible, your writing or typing gets sloppier the faster you try to go. Viral polymerases have the same challenge – they’re trying to go fast and thus make more mistakes than your human polymerases.

Why does this matter? This is the cool part – chemists realized that they could use the “sloppiness” of viral polymerases to halt their replication. Similar to typing on a keyboard, the polymerase is spelling out the RNA code using A, U, C, and G nucleoside triphosphates.

Here’s ATP – adenosine triphosphate. This molecule is used for all sorts of things in your cells, and one of those is to be a building block for the synthesis of new RNA molecules.

Now, here’s Remdesivir. It looks different from ATP, but if you look at the part where the rings are, it’s pretty similar. Viral polymerases are sloppy in different ways, and coronavirus polymerases can’t tell the difference between this part of the molecule for the drug and ATP.

The polymerases that make the RNA in your cells prefer ATP over Remdesivir by ~500:1, but Ebola polymerases (the virus that the drug was originally being developed for) can’t tell the difference between the two and use them equally.
ncbi.nlm.nih.gov/pubmed/30987343

This might not seem like a big deal, but it is. Because Remdesivir is a different structure than ATP, it causes problems once the polymerase “types” it into the RNA code that it’s copying. Soon after, it stalls the copying process and no RNA copying means no viral replication.

As a chemist, I have to point out one of the neatest things about this class of drugs – that they’re prodrugs. Looking back to the structures I showed you, you might notice that the left hand parts of the molecules are very different.

That’s because polymerases need these “triphosphates” – molecules with three P atoms surrounded by oxygens. So, the structure I’ve shown you for Remdesivir is not the active drug – it needs to be turned into a triphosphate to function.

Cells can make these triphosphates, but you can’t get them into cells easily from the outside. So, researchers instead make a “prodrug” – see how Remdesivir has one P atom with other stuff attached to it?

Once in the cell, much of this stuff gets cut off to reveal a single P surrounded by oxygen atoms. At that point, other enzymes in the cell can come in and add the remaining two phosphates that are needed. So, the cell does the final steps in making the drug. How cool is that?!?

Remdesivir was initially developed for Ebola and made it to Phase 3 clinical trial. That means that we know its relatively safe to use in humans. At that point, other therapeutics and vaccines took over, and it wasn’t developed further.

However, over the past couple of years, Remdesivir has been shown to have some effect with SARS and MERS, which are in the same coronavirus family as COVID-19. So, scientists thought that the polymerases of COVID-19 could be tricked into using it, too.

This has been looked at for the viral polymerase in a test tube, and the results are pretty promising. However, the true test will be the human clinical trials which are ongoing.
nature.com/articles/s4142…

We’ll all have to stay tuned to find out if Remdesivir is going to be an effective treatment for COVID-19 infection, but now every time you see it mentioned on the news you can think about the super cool chemistry behind how it works!