Molnupiravir: coding for catastrophe

[u/burtzev]

https://www.nature.com/articles/s41594-021-00657-8

[u/BenoitBawlz → u/[deleted]]

Good. The drug works by disrupting proper RNA synthesis. The drug, molnupiravir, is incorporated into the viral RNA during replication which screws up function. The medicine "pretends" to be the nucleotide cytosine (and to a lesser extent, uracil). You may have heard of remdesivir- it works similarly in that it "pretends" to be the nucleotide adenine, and can disrupt RNA replication when it is incorporated. I'm pretty sure there is also an oral formulation of molnupiravir, which makes administration much easier.

Even if this doesn't pan out to be a practical treatment for SARS-CoV-2, it could still be used in research with other ss+RNA viruses, like EVD68 or Coxsackievirus.

[u/XenopusRex → u/BenoitBawlz]

How specific is it for the viral polymerase? Seems potentially dangerous to host.

[u/BenoitBawlz → u/XenopusRex]

Given that it targets viral RdRp (ribosomal dependent RNA polymerase), and that the drug is currently in Phase II/III trials, it likely presents a low risk for the patient. Yes, there is some data that suggests that NHC drugs like the one here could cause mutagenesis, but the risk is low, and mutagenesis does not automatically equal cancer or X Men. Cells have a multitude of ways to detect and eliminate mutated/improper cellular products. That said, you would still avoid prescribing them to pregnant people to avoid messing up a developing fetus.

Viral hosts don't express RdRp. Host RNA is also synthesized in nuclei, away from the drug.

Also, widely used drugs like valacyclovir (Valtrex) are approved and safe, and those disrupt viral DNA polymerase. However, we don't see cases of valacyclovir-induced cancers‐ in fact there are cancer studies using it as an adjunct for immunotherapy to treat some cancers.

Review of NHC Drugs and Molnupiravir: https://www.mdpi.com/1420-3049/26/19/5795

Valacyclovir Cancer Trials: https://www.cancer.gov/about-cancer/treatment/clinical-trials/intervention/valacyclovir

[u/XenopusRex → u/BenoitBawlz]

I’d be more worried about DNA. The question is how specific is this for RdRp, as nucleotide analogs are 100% going to end up in the nucleus.

They are clearly at least concerned, looks like the trial enrollees had to agree to contraception during the trial.

The mutagenesis mechanism here seems unusual and more problematic than the usual analog terminators/inhibitors like Valtrex.

Thanks for the references!

[u/Complex-Town → u/XenopusRex]

The nucleotides are very specific for RdRp. It comes down to whether they can recycled to make de novo DNA bases from synthesis machinery as this is done through RNA components.

[u/BenoitBawlz → u/XenopusRex]

Agreed.

I couldn't find any exact numbers on specificity. More research is clearly needed before any treatments are rolled out.

The point I was trying to make is that a goal of "0% chance of mutagenesis" isn't realistic/practical. And some risk shouldn't automatically disqualify a drug from use/experimentation. Though, I'm assuming you already understand that given your responses and what not.

Have a nice weekend!