P-1079. <i>In Vitro</i> and <i>in Vivo</i> Antiviral Activity of S-892216, a Second-Generation Oral 3CLpro Inhibitor against SARS-CoV-2
Abstract Background COVID-19 caused by SARS-CoV-2 remains a global public health concern. Although oral direct-acting antivirals for COVID-19 (such as molnupiravir, nirmatrelvir/ritonavir, ensitrelvir) were approved for clinical use, there are concerns about drug-drug interactions (DDI) and safety, so development of new therapeutics is needed. In this study, we describe enzyme inhibitory and antiviral activity of S-892216, a second-generation small molecular 3C-like protease (3CLpro) inhibitor. Methods The 3CLpro enzymatic assay was conducted by mass spectrometry system. In vitro antiviral activity was evaluated using VeroE6/TMPRSS2 cells and human airway epithelial cells (hAEC) following infection by several SARS-CoV-2 variants. In vivo efficacy was evaluated using Balb/c mice, intranasally infected with SARS-CoV-2, and S-892216 was orally administered. Results S-892216 showed high 3CLpro inhibitory activity (IC50 = 0.697 nmol/L) and exhibited in vitro antiviral activity against several SARS-CoV-2 strains, including Omicron variants (EC50 = 2.27-12.5 nmol/L in VeroE6/TMPRSS2 cells, EC90 = 2.31-2.41 nmol/L in hAECs). Furthermore, S-892216 suppressed lung virus titer in Balb/c mice infected with SARS-CoV-2 in a dose-dependent manner. Conclusion S-892216 has stronger 3CLpro inhibitory and antiviral activity than approved 3CLpro inhibitors and has been confirmed to be effective in vivo. Due to the strong antiviral activity of S-892216, it is suggested to be effective at low doses in clinical settings. DDI and safety will be evaluated in clinical trials. Disclosures Haruaki Nobori, PhD, Shionogi & Co., Ltd.: Employee|Shionogi & Co., Ltd.: Stocks/Bonds (Private Company) Sho Kawashima, Shionogi & Co., Ltd.: Employee Reiko Dodo, n/a, Shionogi & Co., Ltd.: Employee Yuki Maruyama, PhD, Shionogi & Co., Ltd.: Employee|Shionogi & Co., Ltd.: Stocks/Bonds (Private Company) Takayo Haruna, n/a, Shionogi & Co., Ltd.: Employee Keiichiro Hirai, PhD, Shionogi & Co., Ltd.: Employee Yuto Unoh, PhD, Shionogi & Co., Ltd.: Employee Kenji Nakahara, PhD, Shionogi & Co., Ltd.: Employee Shota Uehara, Ph.D., Shionogi & Co., Ltd.: Employee|Shionogi & Co., Ltd.: Stocks/Bonds (Private Company) ryosuke watari, n/a, Shionogi & Co., Ltd.: Employee tomoyuki kawachi, n/a, Shionogi & Co., Ltd.: Employee yuka Natsume, n/a, Shionogi & Co., Ltd.: Employee katsumoto hata, n/a, Shionogi & Co., Ltd.: Employee yukiko orita, n/a, Shionogi & Co., Ltd.: Employee kae fujisawa, n/a, Shionogi & Co., Ltd.: Employee tetsuya miyano, PhD, Shionogi & Co., Ltd.: Employee hideko kaneda, n/a, Shionogi TechnoAdvance Research Co., Ltd.: Employee taeko kawai, n/a, Shionogi TechnoAdvance Research Co., Ltd.: Employee Kae Inoue, n/a, Shionogi & Co., Ltd.: Stocks/Bonds (Private Company)|Shionogi TechnoAdvance Research CO., Ltd.: employee Akane Hayashi, n/a, Shionogi & Co., Ltd.: Stocks/Bonds (Private Company)|Shionogi TechnoAdvance Research: Employee Takashi Hashimoto, n/a, Shionogi TechnoAdvance Research CO., Ltd.: employee Kazumi Matsumoto, n/a, Shionogi TechnoAdvance Research: Employee Kaoru Baba, n/a, Shionogi TechnoAdvance Research: Employee taichi ueda, PhD, Shionogi & Co., Ltd.: Employee takafumi sato, PhD, Shionogi & Co., Ltd.: Employee|Shionogi & Co., Ltd.: Stocks/Bonds (Private Company) Teruhisa Kato, PhD, Shionogi & Co., Ltd.: employee|Shionogi & Co., Ltd.: Stocks/Bonds (Private Company) Keita Fukao, MD, SHIONOGI and CO., LTD.: Stocks/Bonds (Private Company)
Authors
- Takafumi Sato (ORCID: https://orcid.org/0000-0001-6534-2560)
- Kae Fujisawa
- Yuto Unoh (ORCID: https://orcid.org/0000-0002-5200-7349)
- Tomoyuki Kawachi (ORCID: https://orcid.org/0000-0003-4702-7481)
- Kazumi Matsumoto
- Yasuhiro Natsume
- Sho Kawashima
- Keiichiro Hirai
- Kaoru Baba (ORCID: https://orcid.org/0009-0005-4427-8754)
- Haruaki Nobori (ORCID: https://orcid.org/0000-0001-5735-0843)
- K. Hata
- Hideko Kaneda
- Takakazu Miyano
- Shota Uehara (ORCID: https://orcid.org/0000-0001-5214-8531)
- Ryosuke Watari (ORCID: https://orcid.org/0009-0004-1846-0467)
- Kae Inoue
- Reiko Dodo
- Kenji Nakahara (ORCID: https://orcid.org/0000-0002-2867-0669)
- Yuki Maruyama (ORCID: https://orcid.org/0000-0002-0812-1478)
- Keita Fukao
- Takayo Haruna
- Taichi Ueda
- Teruhisa Kato (ORCID: https://orcid.org/0000-0001-5041-0110)
- Takashi Hashimoto (ORCID: https://orcid.org/0000-0002-7204-8148)
- Akane Hayashi (ORCID: https://orcid.org/0000-0003-3174-6836)
- Taeko Kawai
- Y Orita
Institutions
- Shionogi (Japan) (JP)
- Shionogi (United States) (US)
- Futaba (Japan) (JP)
Publication Details
- Journal
- Open Forum Infectious Diseases
- Published
- 2025-01-29
- DOI
- https://doi.org/10.1093/ofid/ofae631.1267
- Primary Topic
- Synthesis and biological activity
- Type
- article
- Field-Weighted Citation Impact
- 0.00