The preclinical discovery and development of molnupiravir for the treatment of SARS-CoV-2 (COVID-19)

ABSTRACT

Introduction

Molnupiravir (MOV) is a broad-spectrum oral antiviral agent approved for the treatment of COVID-19. The results from in vitro and in vivo studies suggested MOV activity against many RNA viruses such as influenza virus and some alphaviruses agents of epidemic encephalitis. MOV is a prodrug metabolized into the ribonucleoside analog β-D-N⁴-hydroxycytidine. It is incorporated into the viral RNA chain causing mutations impairing coding activity of the virus, thereby inhibiting viral replication.

Areas covered

This review analyzes the in vitro and in vivo studies that have highlighted the efficacy of MOV and the main pre-authorization randomized controlled trials evaluating its safety, tolerability, and pharmacokinetics, as well as its antiviral efficacy against SARS-COV-2 infection.

Expert opinion

MOV is an antiviral agent with an excellent tolerability profile with few drug–drug interactions. Treatment of mild-to-moderate COVID-19 can benefit from MOV administration in the precocious phases of the disease, prior to the trigger of an aberrant immune response responsible for the parenchymal damage to pulmonary and extrapulmonary tissues. However, its suspected mutagenic effect can be a factor limiting its use at least in selected populations and studies on its teratogen effects should be planned before it is authorized for use in the pediatric population or in pregnant women.

KEYWORDS:

• Molnupiravir
• RNA polymerase
• SARS-CoV-2
• oral therapy
• COVID-19
• ?-D-N4-hydroxycytidine

Article highlights

• Nucleoside analogues interacting with RNA-dependent RNA polymerase (RdRp) are successfully employed for the treatment of many viral diseases

• Molnupiravir is a broad-spectrum antiviral agent, which reports a mutagenic effect on the growing RNA chain. It was found to be active against Influenza virus and some coronaviruses including SARS-CoV-2

• Investigations on cellular models demonstrate that molnupiravir metabolite “®-D-N⁴-hydroxycytidine is active against SARS-CoV-2, but its antiviral effects depend on the time lasting from viral inoculum and starting of treatment. Similar findings have been demonstrated in in vivo studies on hamster and ferret models

• The favorable profile of molnupiravir in terms of side effects and low drug interactions is hampered by its mutagenic effects, which should be considered in treating higher people or pregnant women

• Molnupiravir could be the drug of choice for patients with COVID-19 reporting comorbidities requiring multiple pharmacologic treatment at risk for an unfavorable outcome

Funding

This manuscript was not funded.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.