Efficacy comparison of 3CL protease inhibitors ensitrelvir and nirmatrelvir against SARS-CoV-2 in vitro and in vivo
Kuroda et al.
, Efficacy comparison of 3CL protease inhibitors ensitrelvir and nirmatrelvir against SARS-CoV-2 in vitro..
, Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkad027
In Vitro and animal study comparing nirmatrelvir and ensitrelvir, showing similar efficacy in vitro, and equal or better efficacy of ensitrelvir in vivo (with similar unbound-drug plasma concentrations).
Kuroda et al., 10 Feb 2023, Japan, peer-reviewed, 19 authors.
Abstract: J Antimicrob Chemother
Efﬁcacy comparison of 3CL protease inhibitors ensitrelvir and
nirmatrelvir against SARS-CoV-2 in vitro and in vivo
Pharmaceutical Research Division, Shionogi & Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan; 2Research Area
for Drug Candidate Generation II, Shionogi TechnoAdvance Research Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825,
*Corresponding author. E-mail: firstname.lastname@example.org
†These authors contributed equally to this work.
Received 17 October 2022; accepted 18 January 2023
Objectives: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become established in the human population, making the need to develop safe and effective treatments critical. We have developed the
small-molecule antiviral ensitrelvir, which targets the 3C-like (3CL) protease of SARS-CoV-2. This study evaluated
the in vitro and in vivo efﬁcacy of ensitrelvir compared with that of another SARS-CoV-2 3CL PI, nirmatrelvir.
Methods: Cultured cells, BALB/cAJcl mice and Syrian hamsters were infected with various SARS-CoV-2 strains,
including the ancestral strain WK-521, mouse-adapted SARS-CoV-2 (MA-P10) strain, Delta strain and
Omicron strain. Ensitrelvir efﬁcacy was compared with that of nirmatrelvir. Effective concentrations were determined in vitro based on virus-induced cytopathic effects, viral titres and RNA levels. Lung viral titres, nasal turbinate titres, body-weight changes, and animal survival were also monitored.
Results: Ensitrelvir and nirmatrelvir showed comparable antiviral activity in multiple cell lines. Both ensitrelvir
and nirmatrelvir reduced virus levels in the lungs of mice and the nasal turbinates and lungs of hamsters.
However, ensitrelvir demonstrated comparable or better in vivo efﬁcacy than that of nirmatrelvir when present
at similar or slightly lower unbound-drug plasma concentrations.
Conclusions: Direct in vitro and in vivo efﬁcacy comparisons of 3CL PIs revealed that ensitrelvir demonstrated
comparable in vitro efﬁcacy to that of nirmatrelvir in cell culture and exhibited equal to or greater in vivo efﬁcacy
in terms of unbound-drug plasma concentration in both animal models evaluated. The results suggest that ensitrelvir may become an important resource for treating individuals infected with SARS-CoV-2.
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