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Review on molnupiravir as a promising oral drug for the treatment of COVID-19.

ABSTRACT: During the COVID-19 pandemic, various drug candidates have been developed, molnupiravir (MK-4482 and EIDD-2801), which is a new orally anti-viral agent under development for the treatment of COVID-19, is under study in the final stage of the clinical trial. Molnupiravir enhances the replication of viral RNA mutations in animals and humans. Due to the high demand for the synthesis of this drug, it was essential to develop an efficient and suitable synthetic pathway from raw material. In this study, molecular docking analysis on molnupiravir is examined also, the mechanism of action (MOA) and the recent synthetic pathway is reported. This review will be helpful to different disciplines such as medicinal chemistry, organic chemistry, biochemistry, and pharmacology.

SUBMITTER: Zarenezhad E

PROVIDER: S-EPMC8721938 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Review on molnupiravir as a promising oral drug for the treatment of COVID-19.

Zarenezhad Elham E Marzi Mahrokh M

Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents 20220103 2

During the COVID-19 pandemic, various drug candidates have been developed, molnupiravir (MK-4482 and EIDD-2801), which is a new orally anti-viral agent under development for the treatment of COVID-19, is under study in the final stage of the clinical trial. Molnupiravir enhances the replication of viral RNA mutations in animals and humans. Due to the high demand for the synthesis of this drug, it was essential to develop an efficient and suitable synthetic pathway from raw material. In this stud ...[more]

PMID: 35002192

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Project description:BackgroundNew treatments are needed to reduce the risk of progression of coronavirus disease 2019 (Covid-19). Molnupiravir is an oral, small-molecule antiviral prodrug that is active against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).MethodsWe conducted a phase 3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of treatment with molnupiravir started within 5 days after the onset of signs or symptoms in nonhospitalized, unvaccinated adults with mild-to-moderate, laboratory-confirmed Covid-19 and at least one risk factor for severe Covid-19 illness. Participants in the trial were randomly assigned to receive 800 mg of molnupiravir or placebo twice daily for 5 days. The primary efficacy end point was the incidence hospitalization or death at day 29; the incidence of adverse events was the primary safety end point. A planned interim analysis was performed when 50% of 1550 participants (target enrollment) had been followed through day 29.ResultsA total of 1433 participants underwent randomization; 716 were assigned to receive molnupiravir and 717 to receive placebo. With the exception of an imbalance in sex, baseline characteristics were similar in the two groups. The superiority of molnupiravir was demonstrated at the interim analysis; the risk of hospitalization for any cause or death through day 29 was lower with molnupiravir (28 of 385 participants [7.3%]) than with placebo (53 of 377 [14.1%]) (difference, -6.8 percentage points; 95% confidence interval [CI], -11.3 to -2.4; P = 0.001). In the analysis of all participants who had undergone randomization, the percentage of participants who were hospitalized or died through day 29 was lower in the molnupiravir group than in the placebo group (6.8% [48 of 709] vs. 9.7% [68 of 699]; difference, -3.0 percentage points; 95% CI, -5.9 to -0.1). Results of subgroup analyses were largely consistent with these overall results; in some subgroups, such as patients with evidence of previous SARS-CoV-2 infection, those with low baseline viral load, and those with diabetes, the point estimate for the difference favored placebo. One death was reported in the molnupiravir group and 9 were reported in the placebo group through day 29. Adverse events were reported in 216 of 710 participants (30.4%) in the molnupiravir group and 231 of 701 (33.0%) in the placebo group.ConclusionsEarly treatment with molnupiravir reduced the risk of hospitalization or death in at-risk, unvaccinated adults with Covid-19. (Funded by Merck Sharp and Dohme; MOVe-OUT ClinicalTrials.gov number, NCT04575597.).

Project description:Molnupiravir is one of the two coronavirus disease 2019 (COVID-19) oral drugs that were recently granted the emergency use authorization by the Food and Drug Administration (FDA). Molnupiravir is an ester and requires hydrolysis to exert antiviral activity. Carboxylesterases constitute a class of hydrolases with high catalytic efficiency. Humans express two major carboxylesterases (CES1 and CES2) that differ in substrate specificity. Based on the structural characteristics of molnupiravir, this study was performed to test the hypothesis that molnupiravir is preferably hydrolyzed by CES2. Several complementary approaches were used to test this hypothesis. As many as 24 individual human liver samples were tested and the hydrolysis of molnupiravir was significantly correlated with the level of CES2 but not CES1. Microsomes from the intestine, kidney, and liver, but not lung, all rapidly hydrolyzed molnupiravir and the magnitude of hydrolysis was related closely to the level of CES2 expression among these organs. Importantly, recombinant CES2 but not CES1 hydrolyzed molnupiravir, collectively establishing that molnupiravir is a CES2-selective substrate. In addition, several CES2 polymorphic variants (e.g., R180H) differed from the wild-type CES2 in the hydrolysis of molnupiravir. Molecular docking revealed that wild-type CES2 and its variant R180H used different sets of amino acids to interact with molnupiravir. Furthermore, molnupiravir hydrolysis was significantly inhibited by remdesivir, the first COVID-19 drug granted the full approval by the FDA. The results presented raise the possibility that CES2 expression and genetic variation may impact therapeutic efficacy in clinical situations and warrants further investigation. SIGNIFICANCE STATEMENT: COVID-19 remains a global health crisis, and molnupiravir is one of the two recently approved oral COVID-19 therapeutics. In this study, we have shown that molnupiravir is hydrolytically activated by CES2, a major hydrolase whose activity is impacted by genetic polymorphic variants, disease mediators, and many potentially coadministered medicines. These results presented raise the possibility that CES2 expression and genetic variation may impact therapeutic efficacy in clinical situations and warrants further investigation.

Project description:BackgroundThroughout the time of the global pandemic of SARS-CoV-2 virus, there has been a compelling necessity for the development of effective antiviral agents and prophylactic vaccines to limit the virus spread, disease burden, hospitalization, and mortality. Until mid of 2021, the NIH treatment guideline declared no single oral therapy was proven to treat mild to moderate cases. A new hope arose when a repurposed direct acting oral anti-viral agent "Molnupiravir" was shown to be effective in decreasing mortality and need for hospitalization in mild to moderate cases with relatively good safety profile; exhibiting a significant reduction in virus titers only after two days from administration. Molnupiravir recently granted the FDA emergency use authorization to treat mild to moderate COVID-19 patients with at least one risk factor for progression.MethodsWe performed a computer-based literature search of (PubMed, Science direct, MedRxiv, BioRxiv, ClinicalTrials.gov, ISRCTN, Cochrane COVID study register, EU registry, and CTRI registry) till February 15th, 2022. The following keywords were used in our search ("Molnupiravir", "NHC", "EIDD-2807", "MK-4482" or "EIDD-1931").ResultsWe identified from the initial search a total of 279 articles; 246 articles (BioRxiv and MedRxiv N = 186, PubMed N = 33, Science direct N = 27) and 33 Clinical trials from the following registries (ISCTRN (N = 1), Clinical Trials.gov (N = 6), CTRI (N = 12), Cochrane (N = 14)). Through screening phases, 21 records were removed as duplicates and 198 irrelevant records were also excluded. The included studies in this systematic review were (N = 60) included 39 published papers and 21 clinical trials. After Manual addition (N = 4), the qualitative assessment included (N = 64).ConclusionBased on the cumulative evidence from preclinical and clinical studies, Molnupiravir is proven to be a well tolerated, direct acting oral anti-viral agent to halt the disease progression in mild to moderate COVID-19 cases; in terms of mortality and hospitalization rates.

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Review on molnupiravir as a promising oral drug for the treatment of COVID-19.

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Review on molnupiravir as a promising oral drug for the treatment of COVID-19.

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