SARS-CoV-2 Omicron variant is highly sensitive to molnupiravir, nirmatrelvir, and the combination

Li, Pengfei; Wang, Yining; Lavrijsen, Marla; Lamers, Mart M.; Vries, Annemarie C. de; Rottier, Robbert J.; Bruno, Marco J.; Peppelenbosch, Maikel P.; Haagmans, Bart L.

doi:10.1038/s41422-022-00618-w

Cited by 178 publications

(190 citation statements)

References 13 publications

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“…These observations are consistent with recently reported biochemical characterization with similar kcat/Km and nirmatrelvir potency values (10, 11). Nirmatrelvir also appears to retain its in vitro antiviral efficacy against Omicron relative to wildtype (12–15).…”

Section: Discussionmentioning

confidence: 99%

Structural basis for Nirmatrelvir in vitro efficacy against SARS-CoV-2 variants

Greasley

Noell

Plotnikova

et al. 2022

Preprint

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The COVID-19 pandemic continues to be a public health threat with emerging variants of SARS-CoV-2. Nirmatrelvir (PF-07321332) is a reversible, covalent inhibitor targeting the main protease (Mpro) of SARS-CoV-2 and the active protease inhibitor in PAXLOVID (nirmatrelvir tablets and ritonavir tablets). One of the predominant SARS-CoV-2 variants emerging is the B.1.1.529 Omicron harboring a mutation at amino acid position 132 in the Mpro changing a proline to a histidine (P132H). In vitro biochemical enzymatic assay characterization of the enzyme kinetics of the Omicron Mpro (P132H) demonstrate that it is catalytically comparable to wildtype and that nirmatrelvir has similar potency against both wildtype and Omicron (P132H) Mpro with Ki of 0.933nM (wildtype) and 0.635nM (P132H) each, respectively. This observation is reinforced by our structural determination of nirmatrelvir bound to the omicron Mpro at 1.63Å resolution. These in vitro data suggest that PAXLOVID has the potential to maintain plasma concentrations of nirmatrelvir many-fold times higher than the amount required to stop the SARS-CoV-2 variant Omicron from replicating in cells.

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Section: Discussionmentioning

confidence: 99%

Structural basis for Nirmatrelvir in vitro efficacy against SARS-CoV-2 variants

Greasley

Noell

Plotnikova

et al. 2022

Preprint

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“…Other antiviral like remdesivir and biological agents (convalescent plasma or monoclonal antibodies), which require infusion during a clinical visit, suggest the benefits of molnupiravir for a broader distribution, being an orally efficacious agent and being more acceptable to the patient (Kim et al 2020 ). Molnupiravir has also been shown to be effective against additional versions of SARS-CoV-2, including as the Omicron form, both alone and in combination with nirmatrelvir (Li et al 2022 ). Other variations such as alpha, beta, gamma, and delta were also shown to be molnupiravir-susceptible (Vangeel et al 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Antiviral activity of molnupiravir against COVID-19: a schematic review of evidences

Singla¹,

Goyal²

2022

Bull Natl Res Cent

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Background The study was aimed at encapsulating the evidence of in vitro and in vivo antiviral activities of molnupiravir and its active form against highly pathogenic SARS-CoV-2, the pathogen responsible for COVID-19, and finding out the efficacy and safety of molnupiravir in clinical trials. Main body Information on publications was explored on several databases, gray literature was reviewed, and the outcomes were discussed narratively. Molnupiravir's antiviral efficacy and associated mechanism of action have been verified in vitro against both non-COVID and multiple coronaviruses. Molnupiravir has been tried in preclinical investigations in numerous animal models against non-coronaviruses. Clinical studies in several countries are now being conducted to evaluate its antiviral efficacy in persons infected with COVID-19. The medication displays antiviral effect via generation of copying mistakes during viral RNA replication. Conclusions Molnupiravir is the first oral antiviral medicine to show considerable and convincing antiviral activity in vitro and in animal models. Molnupiravir stops the spread of SARS-CoV-2 in animals that have been infected and in cells grown in a lab. In a clinical research, early molnupiravir treatment reduced hospitalization and death risk in unvaccinated individuals with COVID-19. In the battle against SARS-CoV-2, it could be a potent weapon. However, its role in COVID-19 in moderate to severe cases is still up in the air, and more research is needed.

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“…Molnupiravir inhibited SARS-CoV-2 in cell culture assays, with 50% effective concentrations (EC 50 ) ranging between 0.32 and 2.66 µM [7]. Molnupiravir has broad-spectrum in vitro activity against SARS-CoV-2 variants of concern such as B1.1.529 (omicron) [21][22][23][24][25][26], and B.1.1.7 (alpha), B.1351 (beta), P.1 (gamma) and B.1.617.2 (delta) [7]. The EC 50 values were 1.86-1.95 μM [21], and 1.59, 1.77, 1.32 and 1.68 μM [7], respectively.…”

Section: Pharmacodynamicsmentioning

confidence: 99%

Molnupiravir: First Approval

Syed

2022

Drugs

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Molnupiravir (Lagevrio ® ) is an orally-administered antiviral prodrug that inhibits replication of RNA viruses through viral error induction. It is being developed by Merck and Ridgeback Biotherapeutics for the prevention and treatment of Coronavirus disease 2019 (COVID-19). Molnupiravir received its first approval on 4 November 2021 in the UK for the treatment of mild to moderate COVID-19 in adults with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) diagnostic test and who have at least one risk factor for developing severe illness. Molnupiravir is filed for approval and has emergency use authorization for the treatment of COVID-19 in several countries, including the USA, Japan and those in the EU. This article summarizes the milestones in the development of molnupiravir leading to this first approval for COVID-19. Supplementary Information The online version contains supplementary material available at 10.1007/s40265-022-01684-5.

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SARS-CoV-2 Omicron variant is highly sensitive to molnupiravir, nirmatrelvir, and the combination

Cited by 178 publications

References 13 publications

Structural basis for Nirmatrelvir in vitro efficacy against SARS-CoV-2 variants

Structural basis for Nirmatrelvir in vitro efficacy against SARS-CoV-2 variants

Antiviral activity of molnupiravir against COVID-19: a schematic review of evidences

Molnupiravir: First Approval

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