Viral target and metabolism‐based rationale for combined use of recently authorized small molecule COVID‐19 medicines: Molnupiravir, nirmatrelvir, and remdesivir

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 pro ), 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.

In Vitro Combinatorial Activity of Direct Acting Antivirals and Monoclonal Antibodies against the Ancestral B.1 and BQ.1.1 SARS-CoV-2 Viral Variants

“…While antiviral combination therapy has met with extraordinary success in the treatment of chronic infections, including HIV and HCV, expanding the concept to acute infections such as influenza and COVID-19 has just started to be considered [ 26 , 27 ]. A strong argument for combining drugs with different mechanisms of action is the need to limit the emergence of drug resistance, which is clearly a major issue with persistent viruses.…”

Assessing the mitochondrial safety profile of the molnupiravir active metabolite, β-d-N4-hydroxycytidine (NHC), in the physiologically relevant HepaRG model

“…Unlike uptake, metabolism of NHC is unlikely to contribute to variation in tissue or cell-line specific susceptibility as conversion to the active triphosphate form is efficient and ubiquitous, although the identities of the host kinases responsible for the phosphorylation of NHC are as yet unknown. 41 , 42 Furthermore, differentiated HepaRG cells are non-proliferative meaning lack of proliferation cannot be interpreted as cytotoxicity when using this in vitro model, which may influence IC50 readouts depending on the assay conducted.…”