Thread by @erlichya

Due to popular demand, a thread for the general audience on Molnupiravir, Merck's new treatment for Covid19.

Let's start!

The compound (left) looks like an RNA nucleotide called Cytidine (right) that is found in every cell in nature.

BTW: How do I know it is an RNA nucleotide? You see the two "legs" at the bottom with "OH OH"? If the right leg is OH it is RNA and if it's H, it is DNA. Easy.

The resemblance is nearly perfect except 2 places:
The diff in Blue (isobutylester) is bigger but less important. It's quickly cleaved by an enzyme once the drug is in our body and converted to be identical to a Cytidine.

The "OH" in Red is the magic of this molecule!
Why?

There're 4 four type of nucleotides in the body that are the building blocks for RNA/DNA: Adenosine, Cytidine (our guy ⬆️), Guanine & Thymidine*. In short: C,A,G,T.

The colored part 👇 is the base of the nucleotide and confers its identity.

*In RNA, T is a bit different

The four nucleotides attract each other. The Nitrogen-Hydrogen groups (-NH) are more positive and the Oxygen groups (=O) is more negative.
This creates two complementary pairs:
C goes with G
A goes with T

And this is, my friends, how DNA strand can be replicated!!!

Let's take a moment to appreciate this exciting fact that is the basis of every form of life in this planet.

Back to Molnupiravir!
The addition in red creates a new capability. Like a con artist, Molnupiravir looks like a normal C to the viral replication machinery, which incorporates it to its genome.

But the OH addition induces that pairing with an A instead of with a G! Boom!

We just caused the virus to make a mistake in its genetic code. Every time Molnupiravir is incorporated to its genome, it might put an A instead of G. When there are many mistakes, it cant no longer read its replication machinery and becomes a useless piece of RNA.
🧬➡️🗑️

BTW, many antivirals utilize a similar concept: give a faulty nucleotide to a replicating virus so it will destroy itself in the process. For instance, Remdesivir is a nucleotide that mimics an A, but is supposed to halt the replication machinery instead of mutating the genome.

Look how nicely Molnupiravir inhibits SARS-CoV-2 in a cell line. The x-axis shows growing concentrations of the drug and the y-axis shows the reduction in viral load (up = less virus). Once we rich a critical concentration, all viruses are dead 😍.
Source: science.org/doi/full/10.11…

Interm summary: Molnupiravir is a drug made of RNA. Unlike the vaccines, it isn't a long molecule that encodes a protein. It's just a single nucleotide that acts as a trojan.
Also the doses are different:
Pfizer vax is 0.00003gr/dose
Here is 0.8gr/dose!

https://twitter.com/erlichya/status/1444172920440463360

Why do we need this super-sized dose???
We want that in every target cell (e.g. lung), we will have enough of this nucleotide, so a replicating virus will incorporate it with high probability and commit a suicide.

This brings us to talk about the safety of Molnupiravir.

One worry is that the human cell will also incorporate this nucleotide to their genome, creating mutations. Indeed, this is an RNA nucleotide but there are enzymes that can convert it to a DNA form.

1 At least one manuscript reported that cell cultures can mutated due to this drug.
2 The former head of @BARDA, @RickABright also expressed concerns in his whistleblower letter.
3 Merck excluded pregnant women from their trial.

But is the drug unsafe?
academic.oup.com/jid/article/22…

Not essentially. It might be that a short exposure is totally OK. However, it will be interesting to see the safety data that @Merck presents to the @US_FDA and how they excluded any long term risks, especially for relatively young patients.

The second worry is the induction of new viral strains. Essentially, we are increasing the mutation rate of the virus! Is it a problem?
I am less worried about this one. Viruses optimized their mutation rate. Too slow=static target. Too fast=destroying themselves.

However, I would love to see the sequencing results of viruses from a patient with partial compliance (for instance someone who took only one pill out of the ten recommended ones). Again, let's wait for more data.

Final thought: some people asked me whether Molnupiravir is similar to Ivermectin. The answer is NOT AT ALL. Ivermectin is not a nucleotide and is not incorporated to viral genome. It works against parasites by going after an ion channels that viruses don't have.

Summary:
Molnupiravir is a good step forward but not a magic. The results are nice but it will be interesting to see the FDA decision including the safety profile.

And between this or a vaccine, I will definitely go with the vaccine.