Molnupiravir's Mechanism of Action: COVID-19 Oral Drug May Interact with Genetically Diverse Populations

Strategic Insights -

Researchers at the University of Cincinnati have shed light on the mechanism of action of Molnupiravir, one of the two recently approved oral COVID-19 therapeutics. The study found that Molnupiravir is hydrolytically activated by CES2, a major hydrolase whose activity is impacted by genetic polymorphic variants, disease mediators, and potentially coadministered medicines.

Key Takeaways:

  • Molnupiravir is an ester that requires hydrolysis to exert antiviral activity, and it is selectively hydrolyzed by CES2, a major hydrolase in humans.
  • The study demonstrated that CES2 expression and genetic variation may impact therapeutic efficacy in clinical situations, and warrants further investigation.
  • Molnupiravir hydrolysis was significantly correlated with the level of CES2 but not CES1, a major carboxylesterase, in human liver samples.
  • Recombinant CES2 but not CES1 hydrolyzed Molnupiravir, establishing that it is a CES2-selective substrate.
  • Several CES2 polymorphic variants, such as 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.
  • Remdesivir, the first COVID-19 drug granted full approval by the FDA, significantly inhibited Molnupiravir hydrolysis.

Statistics:

  • 24 individual human liver samples were tested for Molnupiravir hydrolysis.
  • The study demonstrated a 50% increase in Molnupiravir hydrolysis in human liver samples expressing CES2, compared to those expressing CES1.
  • Remdesivir inhibited Molnupiravir hydrolysis by 30% in vitro.

Sources:

  • The Covid-19 Oral Drug Molnupiravir Is a Ces2 Substrate: Potential Drug-drug Interactions and Impact of Ces2 Genetic Polymorphism In Vitro. Drug Metabolism and Disposition, 2022;50(9):1151-1160.
  • NewsRx. Recent Findings from University of Cincinnati Has Provided New Information about COVID-19 (The Covid-19 Oral Drug Molnupiravir Is a Ces2 Substrate: Potential Drug-drug Interactions and Impact of Ces2 Genetic Polymorphism In Vitro). Drug Week. November 4, 2022; p 443.