Israeli-Harvard mathematical model evaluates safety of anti-COVID-19 drug

A collaboration between the Weizmann Institute in Israel and Harvard University developed a mathematical model to test the safety of a class of anti-viral drugs that accelerate the mutation rate of the virus, causing “death by mutagenesis.”

The results, published on the scientific website bioRxiv March 10, find the drug Molnupiravir “narrowly evolutionarily safe, subject to the current estimate of parameters.” Molnupiravir is an FDA-approved treatment for COVID-19. 

“Evolutionary safety can be improved by restricting treatment to individuals with a low clearance rate and by designing treatments that lead to a greater increase in mutation rate,” the authors write. Clearance rate refers to the time it takes for the immune system to reduce viral load.

Death by mutagenesis

Nucleoside analogs are a class of anti-viral drugs, which are chemically similar to the real nucleosides––adenosine, guanine cytosine, and thymine––that form the base pairs of the DNA molecule. 

Some small differences designed into the analogs, however, can hinder the viral genome chain from forming in various ways, and may prevent the formation of the base pairs essential for the DNA to function. 

The result is that the viral mutation rate speeds up, increasing the probability that dangerous mutations will occur and lead to what scientists call “death by mutagenesis” of the virus. 

Assessing risk

One concern about the use of nucleoside analogs is that it might accelerate the evolution of the SARS CoV-2-producing mutant strains with greater virulence. 

Led by mathematical biologist Martin Nowak at Harvard, the authors created a mathematical model that describes the increase and decrease in viral load after infection and derives expressions for the total amount of wild-type and mutant strains produced over the course of the illness. Empirical data on the COVID-19 pandemic and bioinformatic data on the virus are used to estimate key parameters.

Treatment with nucleoside analogs, known as mutagenic, decreases the total viral load by causing lethal mutations in the virus. It can also decrease the number of mutants for two reasons, authors point out, “since (1) it eliminates the ancestors of viable mutants and (2) it accelerates the demise of their offspring by inducing lethal mutations.”

Mutagenic treatment also provides substantial benefits to immunocompromised individuals who enter care with a high cumulative virus load and have a low clearance rate for infection. 

In the non-immunocompromised, “the positive effect of mutagenic treatment on reducing load is smaller and the abundance of mutant virus can even be increased,” the authors write. 

This leads to the warning to restrict treatment to individuals with a low clearance rate for the virus. 

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G. Lobinska et al. Evolutionary safety of death by mutagenesis, bioRxiv (March 2022). DOI: https://doi.org/10.1101/2022.03.10.483790

https://www.biorxiv.org/content/biorxiv/early/2022/03/10/2022.03.10.483790.full.pdf