Sci Transl Med . S-217622, a SARS-CoV-2 main protease inhibitor, decreases viral load and ameliorates COVID-19 severity in hamsters

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Sci Transl Med


. 2022 Nov 3;eabq4064.
doi: 10.1126/scitranslmed.abq4064. Online ahead of print.
S-217622, a SARS-CoV-2 main protease inhibitor, decreases viral load and ameliorates COVID-19 severity in hamsters


Michihito Sasaki ¹ , Koshiro Tabata ¹ , Mai Kishimoto ¹ , Yukari Itakura ¹ , Hiroko Kobayashi ¹ , Takuma Ariizumi ¹ , Kentaro Uemura ^{1 2 3} , Shinsuke Toba ^{1 2} , Shinji Kusakabe ^{1 2} , Yuki Maruyama ^{1 2} , Shun Iida ⁴ , Noriko Nakajima ⁴ , Tadaki Suzuki ⁴ , Shinpei Yoshida ² , Haruaki Nobori ² , Takao Sanaki ² , Teruhisa Kato ² , Takao Shishido ² , William W Hall ^{5 6 7} , Yasuko Orba ^{1 5} , Akihiko Sato ^{1 2 8} , Hirofumi Sawa ^{1 5 7 8 9}



Affiliations

• PMID: 36327352
• DOI: 10.1126/scitranslmed.abq4064

Abstract

In parallel with vaccination, oral antiviral agents are highly anticipated to act as countermeasures for the treatment of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Oral antiviral medication demands not only high antiviral activity, but also target specificity, favorable oral bioavailability, and high metabolic stability. Although a large number of compounds have been identified as potential inhibitors of SARS-CoV-2 infection in vitro, few have proven to be effective in vivo. Here, we show that oral administration of S-217622 (ensitrelvir), an inhibitor of SARS-CoV-2 main protease (M^pro, also known as 3C-like protease), decreases viral load and ameliorates disease severity in SARS-CoV-2-infected hamsters. S-217622 inhibited viral proliferation at low nanomolar to sub-micromolar concentrations in cells. Oral administration of S-217622 demonstrated favorable pharmacokinetic properties and accelerated recovery from acute SARS-CoV-2 infection in hamster recipients. Moreover, S-217622 exerted antiviral activity against SARS-CoV-2 variants of concern (VOCs), including the highly pathogenic Delta variant and the recently emerged Omicron BA.5 and BA.2.75 variants. Overall, our study provides evidence that S-217622, an antiviral agent that is under evaluation in a phase 3 clinical trial (clinical trial registration no. jRCT2031210350), possesses remarkable antiviral potency and efficacy against SARS-CoV-2 and is a prospective oral therapeutic option for COVID-19.