Decoding molnupiravir-induced mutagenesis in SARS-CoV-2

Abstract

Molnupiravir, a prodrug of the nucleoside derivative β-D- N 4 -hydroxycytidine (NHC), is currently in clinical trials for COVID-19 therapy. However, the biochemical mechanisms involved in molnupiravir-induced mutagenesis had not been explored. In a recent study, Gordon et al. demonstrated that NHC can be incorporated into viral RNA, and subsequently extended and used as template for RNA-dependent RNA synthesis, proposing a mutagenesis model consistent with available virological evidence. Their study uncovers molecular mechanisms by which molnupiravir drives SARS-CoV-2 into error catastrophe.

Efficacy and safety of three new oral antiviral treatment (molnupiravir, fluvoxamine and Paxlovid) for COVID-19：a meta-analysis

“…Recently, molnupiravir, an orally active RdRp inhibitor with a favourable pharmacokinetic profile, has received considerable attention owing to its ability to inhibit SARS-COV-2 replication, remove SARs-COV-2 rapidly, reduce viral load and recover fast [ 4 ]. Molnupiravir is the isopropyl ester prodrug of the ribonucleoside analogue β-D-N4-hydroxycytidine (NHC) [ 9 ]. An in vitro evidence shows that molnupiravir is a potent inhibitor of SARS-CoV-2 replication with an EC50 in the submicromolar range [ 9–11 ]; the effect of this antiviral injection was also observed in animal models [ 9 , 12 , 13 ].…”

SARS-CoV-2 receptor binding domain radio-probe: a non-invasive approach for angiotensin-converting enzyme 2 mapping in mice

“…Since then, no small-molecule antiviral drug targeting the SARS-CoV-2 has been approved worldwide. Merck & Co.‘s Molnupiravir [ 14 ] is currently in the clinical stage, which uses a unique mechanism to destroy the virus. Because its molecular structure is similar to RNA nucleotides, the virus lacks a mechanism to identify them, then mistakes it for qualified material when they replicate, resulting in viral RNA with no biological activity.…”

Treatments for COVID-19: Lessons from 2020 and new therapeutic options

“…In patients with confirmed SARS-CoV-2 infection and symptom onset within 7 days, MPV cleared infectious viruses from nasopharyngeal swabs at day 5 and reduced by 50% the time to elimination of SARS-CoV-2 RNA (14 vs 27 days for placebo) [ 45 ]. However, some concerns have been raised regarding MPV due to its toxicity and potential teratogenic effects [ 40 , 46 ]; a phase 2 trial is currently evaluating its safety and efficacy on SARS-CoV-2 shedding in hospitalized patients. Other repurposed drugs potentially targeting multiple steps of the SARS-CoV-2 life cycle are currently being tested, such as ivermectin (IVM), a broad-spectrum antiparasitic agent with previously reported antiviral activity in vitro [ 47 , 48 , 49 ].…”