Molnupiravir Inhibits Replication of the Emerging SARS-CoV-2 Variants of Concern in a Hamster Infection Model

Abdelnabi, Rana; Foo, Caroline S.; Jonghe, Steven De; Maes, Piet; Weynand, Birgit; Neyts, Johan

doi:10.1093/infdis/jiab361

Cited by 115 publications

(96 citation statements)

References 15 publications

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“…Previous studies have shown that the susceptivity to CatA could be adjusted by modifying the ester moieties of ProTides using diverse amino acids and alcohols groups [14,37,38]. Recently, several nucleoside/nucleotide analogs have been identified as promising candidates against SARS-CoV-2, such as favipiravir [39] and molnupiravir (EIDD-2801) [40]. It is expected that the high susceptivity to CatA can be achieved by applying the ProTide technology to these nucleoside/nucleotide analogs using suitable ester moieties.…”

Section: Discussionmentioning

confidence: 99%

Activation of Tenofovir Alafenamide and Sofosbuvir in the Human Lung and Its Implications in the Development of Nucleoside/Nucleotide Prodrugs for Treating SARS-CoV-2 Pulmonary Infection

Liu

Shi

et al. 2021

Pharmaceutics

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ProTide technology is a powerful tool for the design of nucleoside/nucleotide analog prodrugs. ProTide prodrug design improves cell permeability and enhances intracellular activation. The hydrolysis of the ester bond of a ProTide is a determinant of the intracellular activation efficiency and final antiviral efficacy of the prodrug. The hydrolysis is dictated by the catalytic activity and abundance of activating enzymes. The antiviral agents tenofovir alafenamide (TAF) and sofosbuvir (SBV) are typical ProTides. Both TAF and SBV have also been proposed to treat patients with COVID-19. However, the mechanisms underlying the activation of the two prodrugs in the lung remain inconclusive. In the present study, we profiled the catalytic activity of serine hydrolases in human lung S9 fractions using an activity-based protein profiling assay. We evaluated the hydrolysis of TAF and SBV using human lung and liver S9 fractions and purified enzymes. The results showed that CatA and CES1 were involved in the hydrolysis of the two prodrugs in the human lung. More specifically, CatA exhibited a nearly 4-fold higher hydrolytic activity towards TAF than SBV, whereas the CES1 activity on hydrolyzing TAF was slightly lower than that for SBV. Overall, TAF had a nearly 4-fold higher hydrolysis rate in human lung S9 than SBV. We further analyzed protein expression levels of CatA and CES1 in the human lung, liver, and primary cells of the two tissues using proteomics data extracted from the literature. The relative protein abundance of CatA to CES1 was considerably higher in the human lung and primary human airway epithelial cells than in the human liver and primary human hepatocytes. The findings demonstrated that the high susceptivity of TAF to CatA-mediated hydrolysis resulted in efficient TAF hydrolysis in the human lung, suggesting that CatA could be utilized as a target activating enzyme when designing antiviral ester prodrugs for the treatment of respiratory virus infection.

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Section: Discussionmentioning

confidence: 99%

Activation of Tenofovir Alafenamide and Sofosbuvir in the Human Lung and Its Implications in the Development of Nucleoside/Nucleotide Prodrugs for Treating SARS-CoV-2 Pulmonary Infection

Liu

Shi

et al. 2021

Pharmaceutics

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“…1,3,6 In an animal model, molnupiravir retained full efficacy against SARS-CoV-2 variants of concern. 7 The favorable safety and tolerability profile of molnupiravir seen in preclinical studies and a phase 1 trial provided the needed equipoise for further clinical development. 5,8 The potential of molnupiravir as an antiviral treatment for Covid-19 is being evaluated in two phase 2/3 studies, one in outpatients (MOVe-OUT trial 9,10 ) and the other in hospitalized patients (MOVe-IN trial).…”

Section: Introduction Tmentioning

confidence: 99%

Randomized Trial of Molnupiravir or Placebo in Patients Hospitalized with Covid-19

et al. 2022

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Molnupiravir is an oral agent a metabolite of which has activity against SARS-CoV-2. In a controlled trial in adults hospitalized for Covid-19 who had symptoms for 10 days or less prior to randomization, patients received placebo (n=75) or varying doses of molnupiravir (n=218) administered twice-daily for 5 days. There was no impact of treatment on death. Median time to sustained recovery was 9 days in all groups, with day 29 recovery rates ranging from 81.5%-85.2%. There were no dose-limiting side effects or adverse events.

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“…In another mouse model, molnupiravir significantly exhibited antiviral activity when administered 2 hours before, or 12 or 24 h after SARS-CoV-2 infections (as evidenced by a decline in the pulmonary viral load) and clinical success (as indicated by the returned body weight and improved pulmonary function) during the five-day observation [ 24 ]. As a result, molnupiravir has been shown to be effective against SARS-CoV-2 infections with variants of concern, B.1.1.7 or B.1.351 in hamsters, which was supported by a reduction in the pulmonary viral load, regained body weight, and reduction of disease severity [ 27 ].…”

Section: Molnupiravirmentioning

confidence: 99%

Molnupiravir—A Novel Oral Anti-SARS-CoV-2 Agent

Lee

Hsieh

2021

Antibiotics

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Since December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly resulted in a global pandemic with approximately 4 million deaths. Effective oral antiviral agents are urgently needed to treat coronavirus disease-2019 (COVID-19), block SARS-CoV-2 transmission, and prevent progression to severe illness. Molnupiravir (formerly EIDD-2801), a prodrug of beta-D-N4-hydroxycytidine (EIDD-1931) and an inhibitor of RNA-dependent RNA polymerase, possesses significant activity against SARS-CoV-2. Its prophylactic efficacy has been evidenced in a ferret model. Two phase-I trials (NCT04392219 and NCT04746183) have demonstrated that oral molnupiravir is safe and well-tolerated at therapeutic doses. After five-days of oral molnupiravir therapy, satisfactory efficacies, assessed by eliminating nasopharyngeal virus in patients with early and mild COVID-19, were disclosed in two phase-II trials (NCT04405739 and NCT 04405570). Two phase-II/III trials, NCT04575597 and NCT04575584, with estimated enrollments of 1850 and 304 cases, respectively, are ongoing. The NCT04575597 recently released that molnupiravir significantly reduced the risk of hospitalization or death in adults experiencing mild or moderate COVID-19. To benefit individual and public health, clinical applications of molnupiravir to promptly treat COVID-19 patients and prevent SARS-CoV-2 transmission may be expected.

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Molnupiravir Inhibits Replication of the Emerging SARS-CoV-2 Variants of Concern in a Hamster Infection Model

Cited by 115 publications

References 15 publications

Activation of Tenofovir Alafenamide and Sofosbuvir in the Human Lung and Its Implications in the Development of Nucleoside/Nucleotide Prodrugs for Treating SARS-CoV-2 Pulmonary Infection

Activation of Tenofovir Alafenamide and Sofosbuvir in the Human Lung and Its Implications in the Development of Nucleoside/Nucleotide Prodrugs for Treating SARS-CoV-2 Pulmonary Infection

Randomized Trial of Molnupiravir or Placebo in Patients Hospitalized with Covid-19

Molnupiravir—A Novel Oral Anti-SARS-CoV-2 Agent

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