Atypical Mutational Spectrum of SARS-CoV-2 Replicating in the Presence of Ribavirin
Pilar Somovilla, Carlos García‐Crespo, Brenda Martínez‐González, María Eugenia Soria, Ana Isabel de Ávila, Isabel Gallego, Pablo Mínguez, Antoni Durán‐Pastor, Cristina Ferrer‐Orta, Llanos Salar‐Vidal, Mario Esteban‐Muñoz, Sonia Zúñiga, Isabel Sola, Luis Enjuanes, Jaime Esteban, R. Fernández‐Roblas, Ignacio Gadea, Jordi Gómez, Núria Verdaguer, Esteban Domingo, Celia Perales
Abstract
We report that ribavirin exerts an inhibitory and mutagenic activity on SARS-CoV-2-infecting Vero cells, with a therapeutic index higher than 10. Deep sequencing analysis of the mutant spectrum of SARS-CoV-2 replicating in the absence or presence of ribavirin indicated an increase in the number of mutations, but not in deletions, and modification of diversity indices, expected from a mutagenic activity. Notably, the major mutation types enhanced by replication in the presence of ribavirin were A→G and U→C transitions, a pattern which is opposite to the dominance of G→A and C→U transitions previously described for most RNA viruses. Implications of the inhibitory activity of ribavirin, and the atypical mutational bias produced on SARS-CoV-2, for the search for synergistic anti-COVID-19 lethal mutagen combinations are discussed.