Discovery of S-217622, a Non-Covalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19

Unoh, Yuto; Uehara, Shota; Nakahara, Kenji; Nobori, Haruaki; Yamatsu, Yukiko; Yamamoto, Shigeo; Maruyama, Yuki; Taoda, Yoshiyuki; Kasamatsu, Koji; Suto, Takahiro; Kouki, Kensuke; Nakahashi, Atsufumi; Kawashima, Sho; Sanaki, Takao; Toba, Shinsuke; Uemura, Kentaro; Mizutare, Tohru; Ando, Soichiro; Sasaki, Michihito; Orba, Yasuko; Sawa, Hirofumi; Sato, Akihiko; Sato, Takafumi; Kato, Takamasa; Tachibana, Yuki

doi:10.1101/2022.01.26.477782

Cited by 35 publications

(51 citation statements)

References 37 publications

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“…Shionogi recently published the 2/3 phase clinical trial results (phase 2a) of its oral drug S-217622, which is the first non-peptidic, non-covalent SARS-CoV-2 M pro inhibitor for treating COVID-19 clinically. Compare with PF-07321332, S-217622 displayed favorable drug metabolism and pharmacokinetic (DMPK) profiles [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Discovery of 4′-O-methylscutellarein as a potent SARS-CoV-2 main protease inhibitor

Yan

Wang

et al. 2022

Biochemical and Biophysical Research Communications

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Section: Discussionmentioning

confidence: 99%

Discovery of 4′-O-methylscutellarein as a potent SARS-CoV-2 main protease inhibitor

Yan

Wang

et al. 2022

Biochemical and Biophysical Research Communications

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“…S-217622 (fumaric acid co-crystal form) and Nirmatrelvir were synthesized by Shionogi & Co., Ltd. 9 . MPV and remdesivir were obtained from MedChemExpress.…”

Section: Methodsmentioning

confidence: 99%

“…Because these proteases play essential roles in the intracellular amplification stage of SARS-CoV-2 and lack human homologues, they are ideal targets for specific antivirals 6–8 . S-217622, a novel small-molecule inhibitor for SARS-CoV-2 M pro , has been identified through large-scale screening and structure-based optimization 9 (Fig. 1a).…”

Section: Mainmentioning

confidence: 99%

Oral administration of S-217622, a SARS-CoV-2 main protease inhibitor, decreases viral load and accelerates recovery from clinical aspects of COVID-19

Sasaki

Tabata

Kishimoto

et al. 2022

Preprint

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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, a novel inhibitor of SARS-CoV-2 main protease (Mpro, also known as 3C-like protease), decreases viral load and ameliorates the 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 eminent 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 variant. Overall, our study provides evidence that S-217622, an antiviral agent that is under evaluation in a phase II/III clinical trial, possesses remarkable antiviral potency and efficacy against SARS-CoV-2 and is a prospective oral therapeutic option for COVID-19.

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“…Molnupiravir, an inhibitor of the RNA-dependent RNA polymerase of SARS-CoV-2, and nirmatrelvir 39 , an inhibitor of the main protease (also called 3CLpro) of SARS-CoV-2, have been authorized for emergency use by the FDA to treat COVID-19. In addition, S-217622, another inhibitor of 3CLpro, is currently in clinical trials 37,40 . We assessed the therapeutic e cacy of these compounds in hamsters infected with BA.2 (NCD1288).…”

Section: Ba2 and Ba1 Omicron Variants Show Similar Replication And Pa...mentioning

confidence: 99%

Characterization and antiviral susceptibility of SARS-CoV-2 Omicron/BA.2

Kawaoka

Uraki

Kiso

et al. 2022

Preprint

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The recent emergence of SARS-CoV-2 Omicron variants possessing large numbers of mutations has raised concerns of decreased effectiveness of current vaccines, therapeutic monoclonal antibodies, and antiviral drugs for COVID-19 against these variants1,2. While the original Omicron lineage, BA.1, has become dominant in many countries, BA.2 has been detected in at least 67 countries and has become dominant in the Philippines, India, and Denmark. Here, we evaluated the replicative ability and pathogenicity of an authentic infectious BA.2 isolate in immunocompetent and human ACE2 (hACE2)-expressing mice and hamsters. In contrast to recent data with chimeric, recombinant SARS-CoV-2 strains expressing the spike proteins of BA.1 and BA.2 on an ancestral WK-521 backbone3, we observed similar infectivity and pathogenicity in mice and hamsters between BA.2 and BA.1, and less pathogenicity compared to early SARS-CoV-2 strains. We also observed a marked and significant reduction in the neutralizing activity of plasma from COVID-19 convalescent individuals and vaccine recipients against BA.2 compared to ancestral and Delta variant strains. In addition, we found that some therapeutic monoclonal antibodies (REGN10987/REGN10933, COV2-2196/COV2-2130, and S309) and antiviral drugs (molnupiravir, nirmatrelvir, and S-217622) can restrict viral infection in the respiratory organs of hamsters infected with BA.2. These findings suggest that the replication and pathogenicity of BA.2 is comparable to that of BA.1 in rodents and that several therapeutic monoclonal antibodies and antiviral compounds are effective against Omicron/BA.2 variants.

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Discovery of S-217622, a Non-Covalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19

Cited by 35 publications

References 37 publications

Discovery of 4′-O-methylscutellarein as a potent SARS-CoV-2 main protease inhibitor

Discovery of 4′-O-methylscutellarein as a potent SARS-CoV-2 main protease inhibitor

Oral administration of S-217622, a SARS-CoV-2 main protease inhibitor, decreases viral load and accelerates recovery from clinical aspects of COVID-19

Characterization and antiviral susceptibility of SARS-CoV-2 Omicron/BA.2

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