4 ms·
Interesting article, but it could have done a better job of explaining the chemistry. Remdesivir is a prodrug, meaning it must be metabolized (chemically proce
by aazaa 6y ago
Interesting article, but it could have done a better job of explaining the chemistry.
Remdesivir is a prodrug, meaning it must be metabolized (chemically processed) in the body to the active form. Think of it like this:
R-OPX -> R-OH -> R-OPPP
where OPPP is the triphosphate and X is the thing the body hacks off. R-OPPP is the active form of Remdesivir. Your body must perform the net reaction R-OPX -> R-OPPP before it can use the drug.
GS-441524 is R-OH in the above equation.
X is non-trivial to build and install, and it looks like it required a lot of work.
But as these things often happen, nature doesn't give e hoot about the medicinal chemist's net-o hypothesis (R-OPX is better) and does what it will do. It turns out the fancy targeting component PX isn't necessary for efficacy in animals. You get even better results using plain old R-OH.
Even better, R-OH is the starting material for R-OPX, so you save yourself some reactions to boot.
At this point a lesson pops up that gets forgotten time and again in drug discovery programs:
ALWAYS RUN THE CONTROL IN ANIMALS - RUN IT EARLY. NO EXCEPTIONS AND NO EXCUSES!
Also, there is enormous resistance to running the control, because of course it can't work - it's the control and doesn't conform to the neat-o hypothesis.
In this case, the control is R-OH. It was run, but not early enough it seems to prevent the R-OPX train from leaving the station. Once a team starts running with a compound it can be very difficult to pull them back.
Now, this is just speculation taking the article as gospel. It's almost impossible to know for sure what really happens inside drug companies because the trade secret/IP protection culture is so ingrained. Not only that, but I could be misinterpreting the facts presented in the article.
Of course, none of this addresses the main problem with Remdesivir: it can't be orally dosed. You need to get injected multiple times. And that's probably going to be in a clinic, and done by people wearing full PPE. An oral drug would allow you to buy pills and convalesce at home, conserving valuable hospital resources.
As an aside, you typically use a prodrug because you think it will lead to better drug properties than the parent compound. An interesting example is the case of Claritin/Clarinex. The former is the prodrug form of the latter. It turns out the latter is at least as good if not better than the prodrug. Another case of not running the control early, I suspect.
- lbeltrame 6y ago> An oral drug would allow you to buy pills and convalesce at home, conserving valuable hospital resources. That's why the new results (sadly without proper placebo) of lopinavir/ritonavir/ribavirin that came out are interesting (IIRC, they can be administered orally). The first studies (published in NEJM) flopped completely, likely because they were administered too late (as noted by the authors themselves). The new study on Lancet tells that the tide can be turned if they're administered within 7 days of symptom onset. Unfortunately, the authors did not use a placebo arm, and compared the cocktail alone against cocktail + subcutaneous injection of interferon-beta. The latter seems better, but as I said before, we don't know if it's identical to "no administration". The current trials in the USA and China of favipiravir (Avigan), which seemed to halve hospital stay in a small (80 patients) Chinese study suffer from the same problem, as they're compared to standard of care (which means loads of things). I don't know anything about the Phase III study started in Japan, though.
- maxerickson 6y agoYour first 6 paragraphs are not clearer than the article: Some background: Remdesivir works by interfering with the cellular machinery that allows viruses to replicate inside a human host. It is a pro-drug, meaning it must be metabolized and undergo a sequence of five bioactivation steps before it becomes GS-441524 triphosphate, the active compound that impedes viral replication. Remdesivir isn’t Gilead’s only antiviral nucleoside analogue. The company has also developed GS-441524, another pro-drug that, as its name suggests, the body also converts into GS-441524 triphosphate, but in just in three steps. GS-441524 is easier to synthesize than remdesivir, requiring three steps instead of the seven needed for remdesivir. You've omitted the "antiviral nucleoside analogue" jargon but run off into the weeds relative to the comparisons of the number of bioactivation and synthesis steps.
- a1369209993 6y ago> ALWAYS RUN THE CONTROL IN ANIMALS - RUN IT EARLY. NO EXCEPTIONS AND NO EXCUSES! Rather, always run the trial in animals (and early). If you don't have both a control group and a experimental group, you don't have a trial.
- refurb 6y agoAs an aside, you typically use a prodrug because you think it will lead to better drug properties than the parent compound. This is really key. Sometimes you make a prodrug because the active drug isn't soluble enough or you can't crystalize it nicely or it unstable and degrades quickly. The Claritin example is a good one. The prodrug requires metabolism into the active compound, but genetic variation can mean some people don't metabolize it well. There are also interactions with other drugs too. So they just changed to the active drug.