Paxlovid Resistance: Is It Just a Matter of Time Now?

[Nevilledog]

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David Wallace-Wells
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“Pfizer’s coronavirus protease inhibitor Paxlovid being widely used now, and it’s been clear since the beginning that resistant strains of the virus could appear against it. After all, that’s what viruses do.”
science.org
Paxlovid Resistance: Is It Just a Matter of Time Now?
5:47 AM · Jul 12, 2022

https://www.science.org/content/blog-post/paxlovid-resistance-it-just-matter-time-now

Pfizer’s coronavirus protease inhibitor Paxlovid (nirmatrelvir and ritonavir) is being widely used now, and it’s been clear since the beginning that resistant strains of the virus could appear against it. After all, that’s what viruses do. With their vast numbers, fast generation time, and number of mutations, resistance to a given small molecule is generally just a matter of “when”, not “if”. The usual way around this problem is to try to use a drug cocktail, hitting the pathogen simultaneously with compounds that target more than one mechanism. That’s the idea behind the two most successful small-molecule viral therapies we have, against HIV and Hepatitis C.

The exact equivalent for the coronavirus would be to use a protease inhibitor like Paxlovid along with a viral polymerase inhibitor. That’s how Merck’s molnupiravir works, but unfortunately clinical trials showed that it doesn’t work all that well. Still, a combination of the two might be quite valuable, but I have yet to hear of any clinical activity whatsoever that is looking at this - nor have I yet heard of a good explanation for why there isn’t any. At least it seems to work in mice! As it stands, it looks like various parts of the world are using one or using the other, which sounds like a good way to generate resistant strains in all directions, should one have some perverse desire to do that.

Here's a good article here at Science that looks at the situation as of about two weeks ago, and lays out the general story very well. And here’s a new paper looking at the structure of the coronavirus main protease (MPro) with an eye to where such resistant variants might develop. The authors identify amino acids 45-51 in general, along with several other residues (M165, L167, P168, R188, and Q189) that can also affect the active binding site. (For those outside the molecular biology field, that notation uses the single-letter amino acid abbreviations along with the numbered position in the protein sequence. For example, “L50F” tells you that the leucine amino acid (L) at position 50 of the protein has been replaced by a phenylalanine (F) amino acid). That’s not an exhaustive list by any means. The regions of the protein that interact directly with the small molecule are 40−44, 45−51, 140−146, 163−169, and 186−192, but there are many examples known of point mutations in some more distant part of a protein that affect the structure of an active site. Predicting those things from first principles is unfortunately generally not feasible. The authors note that mutations in their regions of concern are already known from wild-type sequences in human infection, so they’re at least feasible. They might, in fact, already be contributing to a spectrum of Paxlovid activity among patients taking the drug. Here's a preprint looking at such a list of mutations that are already known from clinical sequencing efforts.

Now, any such mutations can be a tradeoff between the general fitness of an enzyme to do its job and its ability to evade the binding of the small molecule inhibitor. There are surely plenty of mutations that would keep Paxlovid’s protease inhibitor component (nirmatrelvir) from binding at all, but would also keep many of the enzyme’s substrates from binding, either, so those are dead ends, evolutionarily. But what you really don’t want are changes that give you perfectly competent enzyme variants that also shrug off the small-molecule inhibitor, and we’re not in a position to rule such things out yet. As you will see.

*snip*

[Farmer-Rick]

1. Yup things on earth evolve

Well, most things evolve.

Viruses evolve. Do we think they are never changing and just appeared out of thin air? I think most GOPers do.

Thanks for posting this. It is very interesting.

[Johnny2X2X]

2. The country has accepted the current levels

100,000 cases a day with 200-300 daily deaths. The country has accepted this as a permanent situation. If those double there still won't be any notice. Trip[le and we'll see it start to make the news again.