tetano
Editor, Senior Moderator
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[SUP] 1 [/SUP], Koshiro Tabata[SUP] 1 [/SUP], Mai Kishimoto[SUP] 1 [/SUP], Yukari Itakura[SUP] 1 [/SUP], Hiroko Kobayashi[SUP] 1 [/SUP], Takuma Ariizumi[SUP] 1 [/SUP], Kentaro Uemura[SUP] 1 2 3 [/SUP], Shinsuke Toba[SUP] 1 2 [/SUP], Shinji Kusakabe[SUP] 1 2 [/SUP], Yuki Maruyama[SUP] 1 2 [/SUP], Shun Iida[SUP] 4 [/SUP], Noriko Nakajima[SUP] 4 [/SUP], Tadaki Suzuki[SUP] 4 [/SUP], Shinpei Yoshida[SUP] 2 [/SUP], Haruaki Nobori[SUP] 2 [/SUP], Takao Sanaki[SUP] 2 [/SUP], Teruhisa Kato[SUP] 2 [/SUP], Takao Shishido[SUP] 2 [/SUP], William W Hall[SUP] 5 6 7 [/SUP], Yasuko Orba[SUP] 1 5 [/SUP], Akihiko Sato[SUP] 1 2 8 [/SUP], Hirofumi Sawa[SUP] 1 5 7 8 9 [/SUP]
Affiliations
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[SUP]pro[/SUP], 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.
. 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[SUP] 1 [/SUP], Koshiro Tabata[SUP] 1 [/SUP], Mai Kishimoto[SUP] 1 [/SUP], Yukari Itakura[SUP] 1 [/SUP], Hiroko Kobayashi[SUP] 1 [/SUP], Takuma Ariizumi[SUP] 1 [/SUP], Kentaro Uemura[SUP] 1 2 3 [/SUP], Shinsuke Toba[SUP] 1 2 [/SUP], Shinji Kusakabe[SUP] 1 2 [/SUP], Yuki Maruyama[SUP] 1 2 [/SUP], Shun Iida[SUP] 4 [/SUP], Noriko Nakajima[SUP] 4 [/SUP], Tadaki Suzuki[SUP] 4 [/SUP], Shinpei Yoshida[SUP] 2 [/SUP], Haruaki Nobori[SUP] 2 [/SUP], Takao Sanaki[SUP] 2 [/SUP], Teruhisa Kato[SUP] 2 [/SUP], Takao Shishido[SUP] 2 [/SUP], William W Hall[SUP] 5 6 7 [/SUP], Yasuko Orba[SUP] 1 5 [/SUP], Akihiko Sato[SUP] 1 2 8 [/SUP], Hirofumi Sawa[SUP] 1 5 7 8 9 [/SUP]
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[SUP]pro[/SUP], 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.