I'm not familiar with the synthesis development of remdesivir, but typically those side groups are discovered through a process called Structure Activity Relationship (SAR). The basic idea is you start with a bunch of different compounds (like 1000's) and look at their ability to interfere with a specific enzyme in a high-throughput screen. When you rank the 1000's of compounds, some will work better than others. Then you compare the structures of the top hits and look for similarities. So in this case those huge groups attached to the adenosine likley improve binding to the enzyme because they're greasy/hydrophibic.

So then you add different greasy groups to new compounds and screen those. So will be worse, but sometimes some will be better. Then you look at the better ones, like having a nitrile group off the 1' position of the ribose and maybe that started as an amine (I'm making shit up here) and they decided to make it stick further out (IDK).

Anyway, I did some quick looking at it seems like remdesivir is a prodrug that gets modified by other enzymes to become triphosphorylated and then incorporated into the RNA genome of the virus (https://www.nature.com/articles/nature17180/figures/1). So they got super lucky finding it! Check out that paper for the story.

Thanks, I’ll have some reading to do on easter, now :-)

The observation is correct. Remsedivir is a prodrug, the active compound looks like adenosine monophosphate. But that molecule bears too much charge to be able to cross cell membranes. Consequently medicinal chemists put protecting groups on the offending atom, to help the compound get out of the bloodstream and into cells. Once inside, those are cleaved off through nonspecific esterases and the molecule can't get back out.

It's all part of ADMET (absorption, distribution, metabolism, excretion and toxicity) optimization. Pharmacokinetics is an important subject, and that's why you can use the "XY shoved activity in vitro" papers only as starting points.

Thanks for the good explanation of how Remdesivir enters a cell and stays there.

So looking at the wiki page image of Remdesivir [1] I can see that this looks a lot like the sugar-phosphate backbone that is integral to DNA and RNA. If you imagine DNA as a curling ladder, the nucleoside (adenosine) is the steps, and the sugar-phosphate pairs make up the rails on either side of the steps.

The adenosine bit is attached to a five carbon sugar (pentagon with O at top) which is identical to the sugar it would be attached to in RNA. The next thing along is a phosphate with some oxygens double bonded to it, which is part of the "backbone" of DNA. The stuff attached to that phosphate is nothing like DNA or RNA.

Hope this makes sense and provides a little insight for you :)

1. https://en.wikipedia.org/wiki/Remdesivir

It does, thank you!