P-1079. In Vitro and in Vivo Antiviral Activity of S-892216, a Second-Generation Oral 3CLpro Inhibitor against SARS-CoV-2
Authors: Nobori Haruaki , Kawashima Sho , Dodo Reiko , Maruyama Yuki , Haruna Takayo , Hirai Keiichiro , Unoh Yuto , Nakahara Kenji , Uehara Shota , watari ryosuke , kawachi tomoyuki , Natsume yuka , hata katsumoto , orita yukiko , fujisawa kae , miyano tetsuya , kaneda hideko , kawai taeko , Inoue Kae , Hayashi Akane , Hashimoto Takashi , Matsumoto Kazumi , Baba Kaoru , ueda taichi , sato takafumi , Kato Teruhisa , Fukao Keita 
Published: January 2025

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)