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.

The COVID-19 Oral Drug Molnupiravir Is a CES2 Substrate: Potential Drug-Drug Interactions and Impact of CES2 Genetic Polymorphism In Vitro

ABSTRACT Introduction The coronavirus disease 2019 (COVID-19) pandemic has put a strain on global healthcare systems. Despite admirable efforts to develop rapidly new pharmacotherapies, supportive treatments remain the standard of care. Multiple clinical trials have failed due to design issues, biased patient enrollment, small sample sizes, inadequate control groups, and lack of long-term outcomes monitoring. Areas covered This narrative review depicts the current situation around failed and success COVID-19 clinical trials and recommendations in hospitalized patients with COVID-19, oversights and streamlining of clinically effective therapeutics. PubMed, EBSCO, Cochrane Library, and WHO and NIH guidelines were searched for relevant literature up to 5 August 2022. Expert opinion The WHO, NIH, and IDSA have issued recommendations to better clarify which drugs should be used during the different phases of the disease. Given the biases and high heterogeneity of published studies, interpretation of the current literature is difficult. Future clinical trials should be designed to standardize clinical approaches, with appropriate organization, patient selection, addition of control groups, and careful identification of disease phase to reduce heterogeneity and bias and should rely on the integration of scientific societies to promote a consensus on interpretation of the data and recommendations for optimal COVID-19 therapies.

Failed clinical trials on COVID-19 acute respiratory distress syndrome in hospitalized patients: common oversights and streamlining the development of clinically effective therapeutics

Effect of alcohol exposure on the efficacy and Safety of tenofovir alafenamide fumarate, a major medicine Against human immunodeficiency virus.

Infectious pandemics result in hundreds and millions of deaths, notable examples of the Spanish Flu, the Black Death and smallpox. The current pandemic, caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), is unprecedented even in the historical term of pandemics. The unprecedentedness is featured by multiple surges, rapid identification of therapeutic options and accelerated development of vaccines. Remdesivir, originally developed for Ebola viral disease, is the first treatment of COVID-19 (Coronavirus disease 2019) approved by the United States Food and Drug Administration. As demonstrated by in vitro and preclinical studies, this therapeutic agent is highly potent with a broad spectrum activity against viruses from as many as seven families even cross species. However, randomized controlled trials have failed to confirm the efficacy and safety. Remdesivir improves some clinical signs but not critical parameters such as mortality. This antiviral agent is an ester/phosphorylation prodrug and excessive hydrolysis which increases cellular toxicity. Remdesivir is given intravenously, leading to concentration spikes and likely increasing the potential of hydrolysis-based toxicity. This review has proposed a conceptual framework for improving its efficacy and minimizing toxicity not only for the COVID-19 pandemic but also for future ones caused by remdesivir-sensitive viruses.

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One Hyuk Ra

Papers

The nucleoside antiviral prodrug remdesivir in treating COVID-19 and beyond with interspecies significance