tetano
Editor, Senior Moderator
Fundam Clin Pharmacol
. 2023 Mar 17.
doi: 10.1111/fcp.12889. Online ahead of print.
Viral target- and metabolism-based rationale for combined use of recently authorized small molecule COVID-19 medicines: molnupiravir, nirmatrelvir and remdesivir
Daisy Yan[SUP] 1 [/SUP], Bingfang Yan[SUP] 2 [/SUP]
Affiliations
Abstract
The COVID-19 pandemic remains a major health concern worldwide, and SARS-CoV-2 is continuously evolving. There is an urgent need to identify new antiviral drugs and develop novel therapeutic strategies. Combined use of newly authorized COVID-19 medicines including molnupiravir, nirmatrelvir and remdesivir, has been actively pursued. Mechanistically, nirmatrelvir inhibits SARS-CoV-2 replication by targeting the viral main protease (M[SUP]pro[/SUP] ), a critical enzyme in the processing of the immediately translated coronavirus polyproteins for viral replication. Molnupiravir and remdesivir, on the other hand, inhibit SARS-CoV-2 replication by targeting RNA-dependent RNA-polymerase (RdRp), which is directly responsible for genome replication and production of subgenomic RNAs. Molnupiravir targets RdRp and induces severe viral RNA mutations (genome), commonly referred to as error catastrophe. Remdesivir, in contrast, targets RdRp and causes chain termination and arrests RNA synthesis of the viral genome. In addition, all three medicines undergo extensive metabolism with strong therapeutic significance. Molnupiravir is hydrolytically activated by carboxylesterase-2 (CES2); nirmatrelvir is inactivated by cytochrome P450-based oxidation (e.g., CYP3A4); and remdesivir is hydrolytically activated by CES1 but covalently inhibits CES2. Additionally, remdesivir and nirmatrelvir are oxidized by the same CYP enzymes. The distinct mechanisms of action provide strong rationale for their combined use. On the other hand, these drugs undergo extensive metabolism that determines their therapeutic potential. This review discusses how metabolism pathways and enzymes involved should be carefully considered during their combined use for therapeutic synergy.
Keywords: Molnupiravir; RNA-dependent RNA-polymerase; SARS-CoV-2; main protease; nirmatrelvir; remdesivir.
. 2023 Mar 17.
doi: 10.1111/fcp.12889. Online ahead of print.
Viral target- and metabolism-based rationale for combined use of recently authorized small molecule COVID-19 medicines: molnupiravir, nirmatrelvir and remdesivir
Daisy Yan[SUP] 1 [/SUP], Bingfang Yan[SUP] 2 [/SUP]
Affiliations
- PMID: 36931725
- DOI: 10.1111/fcp.12889
Abstract
The COVID-19 pandemic remains a major health concern worldwide, and SARS-CoV-2 is continuously evolving. There is an urgent need to identify new antiviral drugs and develop novel therapeutic strategies. Combined use of newly authorized COVID-19 medicines including molnupiravir, nirmatrelvir and remdesivir, has been actively pursued. Mechanistically, nirmatrelvir inhibits SARS-CoV-2 replication by targeting the viral main protease (M[SUP]pro[/SUP] ), a critical enzyme in the processing of the immediately translated coronavirus polyproteins for viral replication. Molnupiravir and remdesivir, on the other hand, inhibit SARS-CoV-2 replication by targeting RNA-dependent RNA-polymerase (RdRp), which is directly responsible for genome replication and production of subgenomic RNAs. Molnupiravir targets RdRp and induces severe viral RNA mutations (genome), commonly referred to as error catastrophe. Remdesivir, in contrast, targets RdRp and causes chain termination and arrests RNA synthesis of the viral genome. In addition, all three medicines undergo extensive metabolism with strong therapeutic significance. Molnupiravir is hydrolytically activated by carboxylesterase-2 (CES2); nirmatrelvir is inactivated by cytochrome P450-based oxidation (e.g., CYP3A4); and remdesivir is hydrolytically activated by CES1 but covalently inhibits CES2. Additionally, remdesivir and nirmatrelvir are oxidized by the same CYP enzymes. The distinct mechanisms of action provide strong rationale for their combined use. On the other hand, these drugs undergo extensive metabolism that determines their therapeutic potential. This review discusses how metabolism pathways and enzymes involved should be carefully considered during their combined use for therapeutic synergy.
Keywords: Molnupiravir; RNA-dependent RNA-polymerase; SARS-CoV-2; main protease; nirmatrelvir; remdesivir.