24 October 2021

A new anti-viral therapy for SARS-CoV-2 was predicted twenty years ago by evolutionary biologist Mark Ridley

 

Corona update    
24 October 2021    

"We just need to increase the viral mutation rate and they’ll collapse under their own copying errors. The treatment would need selectively to increase the viral, and not the host's, mutation rate, but that should be feasible." Mark Ridley (2000) Mendel's Demon, page 89. [7]

Ridley wrote about his second favourite cure for AIDS. So, this was not about SARS-CoV-2. SARS-CoV-1 and SARS-CoV-2 did not exist in 2000. It was another RNA virus: HIV. But the same evolutionary calculations apply. Ridley did not make a wild guess. He based his claim on his own tentative conclusion that some RNA viruses have evolved near to the limit of complexity set by their copying error rates. That means they have the maximum copy error rate compatible with survival: about 1 copy error per 30,000 bases. At each replication cycle the complete virus is copied (all 30,000 bases). That means that with that error rate a virus of length 30,000 bases would produce 1 copy error at each replication cycle.

According to the recent research the mutation rate of SARS-CoV-2 appears to be 3.7 per million bases per replication cycle [3]. As it happens SARS-CoV-2 has a length of 30,000 bases. Ridley did not know that, but he was close with his estimate. If SARS-CoV-2 lives close to the point of mutational meltdown, than it is quite easy to 'mutate the virus to death'. By 'close to the point of mutational meltdown' I mean only a slight increase in mutation rate will kill the virus. The genetic information in the virus will be destroyed increasingly at each copy cycle. In other words: only a little push will throw the virus into the abyss.

pushing the virus over the edge in to mutational collapse

If the virus is close to the edge (B) only a little push is needed. When it is further away from the edge (A) a strong push is needed.

Nature 8 Oct 2021 [1],[2]

So far the theory. How does that translate into a drug? Molnupiravir is the proposed answer. Here is an abbreviated abstract of how the drug works:

Molnupiravir is a nucleoside analogue, which means it mimics some of the building blocks of RNA. When SARS-CoV-2 enters a cell, the virus needs to duplicate its RNA genome to form new viruses. Molnupiravir gets incorporated into burgeoning RNA strands and, once inside, wreaks havoc. The compound can shift its configuration, sometimes mimicking the nucleoside cytidine (C) and sometimes mimicking uridine (U). Those RNA strands become faulty blueprints for the next round of viral genomes. Anywhere the compound gets inserted and that conformational shift happens, a point mutation occurs. When enough mutations accumulate, the viral population collapses. That is lethal mutagenesis. The virus essentially mutates itself to death [1].

In fact this is a practical translation of Ridley's idea: increase the mutation rate and the virus will suffer a mutational meltdown (error catastrophe). How this is achieved is interesting. The base substitute has two configurations: one similar to C and one similar to U. If those configurations occur randomly when incorporated in a RNA sequence, they introduce random mutations when the sequence is copied. Exactly that is the reason that compound does not occur naturally in RNA. It would make the genetic code unreliable. Life cannot be built on an unreliable code.

How strong would be the effect? What dose of the base analogue do we need?  


It would be too optimistic to assume that all suitable bases in the virus genome would be replaced by the drug. Now, there are between 7000 and 8000 of each of the 4 bases U,C,A,G in the virus RNA sequence of 30,000 bases (the length of SARS-CoV-2). Suppose that 10% of the say 7500 C's of a virus genome are replaced by Molnupiravir, that is 750, and when this RNA strand is copied again 50% of the Molnupiravir bases have a different configuration. This would cause 375 new mutations in the copied virus genome. This is really a huge amount when compared with  1 mutation in 3-7 virus replication cycles [6]. Compare this also to an estimated 10-20 mutations in a SARS-CoV-2 variant [8]. This high number of 375 mutations should destroy the function of all produced viral proteins ... if they are produced at all! If too many mutations occur for example in the Spike protein, the virus can't enter a human cell. If too many mutations accumulate in viral RNA polymerase, the virus RNA cannot be copied. 

Further, the effect of the drug will depend on how many of the virus particles will be affected. It would be too optimistic to suppose that all replicating virus particles would be affected. I have no idea what percentage that would be. Anyhow, the unaffected virus particles will replicate at an unrestricted rate. So, it all depends on the dose of the drug. A higher dose should have a stronger effect on the percentage of affected viruses and the percentage of replaced bases in a virus genome. But a higher dose could be toxic to the patient.

Concluding, we could state that 20 yeas ago evolutionary biologist Mark Ridley correctly predicted the possibility of an error catastrophe causing drug such as Molnupiravir.

In June 2021 Molnupiravir received an emergency use authorization of the U.S. Food and Drug Administration (FDA) for therapy of COVID-19 patients. The European Medicines Agency (EMA) is reviewing Molnupiravir.


Thoughts about first RNA replicating molecules ...

The 'RNA world' is a well-known hypothesis about the Origin of Life. I am tempted to think that unreliable, unstable bases could have been used by the very first RNA replicators. By a process of natural selection for stability, the more stable bases would end up in the successful replicators. The unstable bases would become extinct. The 5 bases we now have A,C,T,G,U must have been selected for their stability and became dominant. A personal hypothesis. Data have to be collected and experiments have to be done!


Postscript

20 Nov 2021:  Molnupiravir has been approved by The European Medicines Agency (EMA).


Sources

  1. How antiviral pill molnupiravir shot ahead in the COVID drug hunt, Nature, 8 Oct 2021 
  2. The Merck pill, which could become the first oral antiviral COVID treatment, forces the coronavirus SARS-CoV-2 to mutate itself to death, Scientific American 12 Oct 2021
  3. Vítor Borges et al Mutation rate of SARS-CoV-2 and emergence of mutators during experimental evolution, biorxiv.org (not yet peer-reviewed)
  4. Molnupiravir (wikipedia)
  5. Error catastrophe (wikipedia); Mutational meltdown (wikipedia)
  6. The total number and mass of SARS-CoV-2 virions, PNAS June 22, 2021.
  7. This book is one of the most insightful books about evolution I have ever read. It is reviewed on my website. 
  8. 24 November 2021: a new SARS-CoV-2 variant has been discovered in South Africa: the Omnicron variant (wikipedia). The variant has 51 mutations in total including deletions and 1 insertion. Added Dec 1 2021

 

 



4 comments:

  1. An interesting post Gert,

    Does this mutation rate (mutation rate of 1 in 30,000 per replication cycle) of SARS CoV-2 also include the exonuclease activity of the virus? I mean 1 in 30,000 is the final, total mutation rate per replication cycle?
    I read that SARS CoV-2 has a very large genome (30.000 bases) compared to other RNA viruses and that it has proofreading for that reason.
    Wouldn't it be possible to inhibit this proofreading with a chemical or enzymatic mechanism? They will be eagerly looking for that.

    Here I read the following:
    ExoN is a powerful tool for understanding CoV replication, and a novel and conserved target for inhibition and attenuation

    https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009226

    ReplyDelete
  2. Hi Marleen, nice to have you back! I hope all is well with you.

    Yes, around the world different research groups try different strategies to inhibit virus replication. Indeed, RNA proofreading exoribonuclease nsp14-ExoN is also a drug target. Probably one or more drugs of that type are in a clinical test phase right now.

    Remarkable statement in your publication: "nsp14-ExoN ... [gives] ... resistance to nucleoside analogues,"!
    Since Molnupiravir is a nucleoside analogue, it means that this drug can overcome the proofreading system of the virus! That is of course a very good property.

    I choose the topic Molnupiravir and error catastrophe because I remember Mark Ridley predicted it 20 years ago, but at the time it was speculation and just theory, but now it is a real anti-viral therapy that has been approved for use in humans! Isn't that wonderful: from pure speculation to approved therapy?
    There aren't any other SARS-CoV-2 drugs that are effective and safe, and approved, so far.

    Thanks for your comment.

    ReplyDelete
  3. Good evening Gert,

    I totally agree with you about Molnupiravir apparently not being bothered by the exonuclease.
    As for the stability of nucleotides, I think you're right, although there will have been all kinds of variations on these 5, methylated or not or having other minor substitutions. There is usually speculation about the stability of RNA and DNA molecules. DNA, which is much more stable, would have been injected into the first cells by DNA viruses, according to Patrick Forterre...you remember, the French microbiologist specialized in viruses that he classified as being alive.

    ReplyDelete
  4. Yes Marleen, I know you like the theory of Patrick Forterre. For me his theory raises more questions than answers.
    For example do you know whether he thinks that viruses originated before cells?
    (viruses first, cells later)?

    ReplyDelete

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