Efficacy comparison of 3CL protease inhibitors ensitrelvir and nirmatrelvir against SARS-CoV-2 in vitro and in vivo

Kuroda et al., Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkad027

Feb 2023

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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).

4 preclinical studies support the efficacy of ensitrelvir for COVID-19:

2 In Vitro studies1,2

2 In Vivo animal studies2,3

In Vitro studies demonstrate efficacy in VeroE6/TMPRSS2A,2, HEK293T/ACE2-TMPRSS2B,2, and MucilAirC,2 cells. Animal studies demonstrate efficacy in BALB/c miceD,2,3 and Syrian hamstersE,2. Preclinical studies demonstrate efficacy for the ancestralF,2, deltaG,2, and omicronH,2 variants.

Important missing comments or errors? Let us know.

Study covers paxlovid and ensitrelvir.

1. Nair et al., Persistence of an infectious form of SARS-CoV-2 post protease inhibitor treatment of permissive cells in vitro, The Journal of Infectious Diseases, doi:10.1093/infdis/jiae385.oup.com, doi.org.

2. Kuroda et al., Efficacy comparison of 3CL protease inhibitors ensitrelvir and nirmatrelvir against SARS-CoV-2 in vitro and in vivo, Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkad027.oup.com, doi.org.

3. Nobori et al., Prophylactic effect of ensitrelvir in mice infected with SARS-CoV-2, Antiviral Research, doi:10.1016/j.antiviral.2024.105852.sciencedirect.com, doi.org.

a. VeroE6/TMPRSS2 is a Vero E6 cell line engineered to express the human serine protease TMPRSS2, enabling SARS-CoV-2 S protein priming and entry.

b. HEK293T/ACE2-TMPRSS2 is a human embryonic kidney cell line engineered to express human ACE2 and TMPRSS2, making it highly susceptible to SARS-CoV-2 infection.

c. MucilAir cells are primary human nasal epithelial cells that mimic the structure and physiology of the human airway epithelium.

d. A mouse model commonly used in infectious disease and cancer research due to higher immune response and susceptibility to infection.

e. A small rodent model used in SARS-CoV-2 research that replicates key aspects of human infection including efficient replication in the upper and lower respiratory tract.

f. The original SARS-CoV-2 strain that emerged in Wuhan, China in late 2019. Also referred to as wild-type.

g. A variant of concern first identified in India in late 2020, delta (B.1.617.2) transmitted more efficiently than previous variants. It contains spike mutations including L452R which increases binding to the ACE2 receptor.

h. A highly transmissible variant of concern first detected in South Africa in late 2021. Omicron possesses many spike mutations which confer partial immune evasion, including deletions near the furin cleavage site.

Kuroda et al., 10 Feb 2023, Japan, peer-reviewed, 19 authors. Contact: takao.shishido@shionogi.co.jp.

This Paper Ensitrelvir All

Efficacy comparison of 3CL protease inhibitors ensitrelvir and nirmatrelvir against SARS-CoV-2 in vitro and in vivo

Takayuki Kuroda, Haruaki Nobori, Keita Fukao, Kaoru Baba, Kazumi Matsumoto, Shinpei Yoshida, Yukari Tanaka, Ryosuke Watari, Ryoko Oka, Yasuyuki Kasai, Kae Inoue, Sho Kawashima, Alice Shimba, Yoko Hayasaki-Kajiwara, Miki Tanimura, Qianhui Zhang, Yuki Tachibana, Teruhisa Kato, Takao Shishido

Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkad027

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.

Supplementary data Supplementary Methods and Figure S1 are available as Supplementary data at JAC Online.

References

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Matsuyama, Nao, Shirato, Enhanced isolation of SARS-CoV-2 by TMPRSS2-expressing cells, Proc Natl Acad Sci U S A, doi:10.1073/pnas.2002589117

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'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'syndication'}, { 'URL': 'https://academic.oup.com/jac/advance-article-pdf/doi/10.1093/jac/dkad027/49151594/dkad027.pdf', 'content-type': 'unspecified', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2023, 2, 10]], 'date-time': '2023-02-10T06:02:24Z', 'timestamp': 1676008944000}, 'score': 1, 'resource': { 'primary': { 'URL': 'https://academic.oup.com/jac/advance-article/doi/10.1093/jac/dkad027/7033725'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2023, 2, 10]]}, 'references-count': 24, 'URL': 'http://dx.doi.org/10.1093/jac/dkad027', 'relation': {}, 'ISSN': ['0305-7453', '1460-2091'], 'subject': ['Infectious Diseases', 'Pharmacology (medical)', 'Pharmacology', 'Microbiology (medical)'], 'published': {'date-parts': [[2023, 2, 10]]}}

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