tetano
Editor, Senior Moderator
J Med Chem
. 2022 Mar 30.
doi: 10.1021/acs.jmedchem.2c00117. Online ahead of print.
Discovery of S-217622, a Noncovalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19
Yuto Unoh[SUP] 1 [/SUP], Shota Uehara[SUP] 1 [/SUP], Kenji Nakahara[SUP] 1 [/SUP], Haruaki Nobori[SUP] 1 [/SUP], Yukiko Yamatsu[SUP] 1 [/SUP], Shiho Yamamoto[SUP] 1 [/SUP], Yuki Maruyama[SUP] 1 2 [/SUP], Yoshiyuki Taoda[SUP] 1 [/SUP], Koji Kasamatsu[SUP] 1 [/SUP], Takahiro Suto[SUP] 1 [/SUP], Kensuke Kouki[SUP] 1 [/SUP], Atsufumi Nakahashi[SUP] 1 [/SUP], Sho Kawashima[SUP] 1 [/SUP], Takao Sanaki[SUP] 1 [/SUP], Shinsuke Toba[SUP] 1 2 [/SUP], Kentaro Uemura[SUP] 1 2 [/SUP], Tohru Mizutare[SUP] 1 [/SUP], Shigeru Ando[SUP] 1 [/SUP], Michihito Sasaki[SUP] 2 [/SUP], Yasuko Orba[SUP] 2 [/SUP], Hirofumi Sawa[SUP] 2 [/SUP], Akihiko Sato[SUP] 1 2 [/SUP], Takafumi Sato[SUP] 1 [/SUP], Teruhisa Kato[SUP] 1 [/SUP], Yuki Tachibana[SUP] 1 [/SUP]
Affiliations
Abstract
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and threatens public health and safety. Despite the rapid global spread of COVID-19 vaccines, effective oral antiviral drugs are urgently needed. Here, we describe the discovery of S-217622, the first oral noncovalent, nonpeptidic SARS-CoV-2 3CL protease inhibitor clinical candidate. S-217622 was discovered via virtual screening followed by biological screening of an in-house compound library, and optimization of the hit compound using a structure-based drug design strategy. S-217622 exhibited antiviral activity in vitro against current outbreaking SARS-CoV-2 variants and showed favorable pharmacokinetic profiles in vivo for once-daily oral dosing. Furthermore, S-217622 dose-dependently inhibited intrapulmonary replication of SARS-CoV-2 in mice, indicating that this novel noncovalent inhibitor could be a potential oral agent for treating COVID-19.
. 2022 Mar 30.
doi: 10.1021/acs.jmedchem.2c00117. Online ahead of print.
Discovery of S-217622, a Noncovalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19
Yuto Unoh[SUP] 1 [/SUP], Shota Uehara[SUP] 1 [/SUP], Kenji Nakahara[SUP] 1 [/SUP], Haruaki Nobori[SUP] 1 [/SUP], Yukiko Yamatsu[SUP] 1 [/SUP], Shiho Yamamoto[SUP] 1 [/SUP], Yuki Maruyama[SUP] 1 2 [/SUP], Yoshiyuki Taoda[SUP] 1 [/SUP], Koji Kasamatsu[SUP] 1 [/SUP], Takahiro Suto[SUP] 1 [/SUP], Kensuke Kouki[SUP] 1 [/SUP], Atsufumi Nakahashi[SUP] 1 [/SUP], Sho Kawashima[SUP] 1 [/SUP], Takao Sanaki[SUP] 1 [/SUP], Shinsuke Toba[SUP] 1 2 [/SUP], Kentaro Uemura[SUP] 1 2 [/SUP], Tohru Mizutare[SUP] 1 [/SUP], Shigeru Ando[SUP] 1 [/SUP], Michihito Sasaki[SUP] 2 [/SUP], Yasuko Orba[SUP] 2 [/SUP], Hirofumi Sawa[SUP] 2 [/SUP], Akihiko Sato[SUP] 1 2 [/SUP], Takafumi Sato[SUP] 1 [/SUP], Teruhisa Kato[SUP] 1 [/SUP], Yuki Tachibana[SUP] 1 [/SUP]
Affiliations
- PMID: 35352927
- DOI: 10.1021/acs.jmedchem.2c00117
Abstract
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and threatens public health and safety. Despite the rapid global spread of COVID-19 vaccines, effective oral antiviral drugs are urgently needed. Here, we describe the discovery of S-217622, the first oral noncovalent, nonpeptidic SARS-CoV-2 3CL protease inhibitor clinical candidate. S-217622 was discovered via virtual screening followed by biological screening of an in-house compound library, and optimization of the hit compound using a structure-based drug design strategy. S-217622 exhibited antiviral activity in vitro against current outbreaking SARS-CoV-2 variants and showed favorable pharmacokinetic profiles in vivo for once-daily oral dosing. Furthermore, S-217622 dose-dependently inhibited intrapulmonary replication of SARS-CoV-2 in mice, indicating that this novel noncovalent inhibitor could be a potential oral agent for treating COVID-19.