The Antiviral Mechanism of Action of Molnupiravir in Humans with COVID-19

Abstract

AbstractMeaningful metrics of antiviral activity are essential for determining the efficacy of therapeutics in human clinical trials. Molnupiravir (MOV) is a broadly acting antiviral nucleoside analog prodrug that acts as a competitive alternative substrate for the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). We developed an assay, Culture-PCR, to better understand the impact of MOV therapy on infectious SARS-CoV-2. Culture-PCR revealed MOV eliminated infectious virus within 48 hours in the nasopharyngeal compartment, the upper airway location with the greatest levels of infectious virus. MOV therapy was associated with increases in mutations across the viral genome but select regions were completely unaffected, thus identifying regions where mutation likely abrogates infectivity. MOV therapy did not alter the magnitude or neutralization capacity of the humoral immune response, a documented correlate of protection. Thus, we provide holistic insights into the function of MOV in adults with COVID-19.