Evolutionary safety of lethal mutagenesis driven by antiviral treatment.
Journal
PLoS biology
ISSN: 1545-7885
Titre abrégé: PLoS Biol
Pays: United States
ID NLM: 101183755
Informations de publication
Date de publication:
08 2023
08 2023
Historique:
received:
07
09
2022
accepted:
23
06
2023
medline:
10
8
2023
pubmed:
8
8
2023
entrez:
8
8
2023
Statut:
epublish
Résumé
Nucleoside analogs are a major class of antiviral drugs. Some act by increasing the viral mutation rate causing lethal mutagenesis of the virus. Their mutagenic capacity, however, may lead to an evolutionary safety concern. We define evolutionary safety as a probabilistic assurance that the treatment will not generate an increased number of mutants. We develop a mathematical framework to estimate the total mutant load produced with and without mutagenic treatment. We predict rates of appearance of such virus mutants as a function of the timing of treatment and the immune competence of patients, employing realistic assumptions about the vulnerability of the viral genome and its potential to generate viable mutants. We focus on the case study of Molnupiravir, which is an FDA-approved treatment against Coronavirus Disease-2019 (COVID-19). We estimate that Molnupiravir is narrowly evolutionarily safe, subject to the current estimate of parameters. Evolutionary safety can be improved by restricting treatment with this drug to individuals with a low immunological clearance rate and, in future, by designing treatments that lead to a greater increase in mutation rate. We report a simple mathematical rule to determine the fold increase in mutation rate required to obtain evolutionary safety that is also applicable to other pathogen-treatment combinations.
Identifiants
pubmed: 37552682
doi: 10.1371/journal.pbio.3002214
pii: PBIOLOGY-D-22-01963
pmc: PMC10409280
doi:
Substances chimiques
Antiviral Agents
0
molnupiravir
YA84KI1VEW
Hydroxylamines
0
Mutagens
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e3002214Informations de copyright
Copyright: © 2023 Lobinska et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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