Synthesis of deuterated S-217622 (Ensitrelvir) with antiviral activity against coronaviruses including SARS-CoV-2

Yujian Yang; Liu Cao; Ming Yan; Jun Zhou; Sidi Yang; Tiefeng Xu; Siyao Huang; Kun Li; Qifan Zhou; Guanguan Li; Yujun Zhu; Feng Cong; Hongmin Zhang; Deyin Guo; Yingjun Li; Xumu Zhang

doi:10.1016/j.antiviral.2023.105586

Synthesis of deuterated S-217622 (Ensitrelvir) with antiviral activity against coronaviruses including SARS-CoV-2

Antiviral Res. 2023 May:213:105586. doi: 10.1016/j.antiviral.2023.105586. Epub 2023 Mar 28.

Authors

Yujian Yang¹, Liu Cao², Ming Yan³, Jun Zhou¹, Sidi Yang⁴, Tiefeng Xu², Siyao Huang², Kun Li², Qifan Zhou¹, Guanguan Li¹, Yujun Zhu⁵, Feng Cong⁵, Hongmin Zhang⁶, Deyin Guo⁷, Yingjun Li⁸, Xumu Zhang⁹

Affiliations

¹ Department of Chemistry, College of Science, Academy for Advanced Interdisciplinary Studies, and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen, Guangdong, 518000, China.
² Centre for Infection and Immunity Studies (CIIS), School of Medicine, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China.
³ Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, Guangdong, 518000, China.
⁴ Guangzhou Laboratory, Bio-island, Guangzhou, Guangdong, 510320, China.
⁵ Guangdong Province Key Laboratory of Laboratory Animals, Guangdong Laboratory Animals Monitoring Institute, Guangzhou, Guangdong, 510663, China.
⁶ Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, Guangdong, 518000, China. Electronic address: [email protected].
⁷ Centre for Infection and Immunity Studies (CIIS), School of Medicine, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China; Guangzhou Laboratory, Bio-island, Guangzhou, Guangdong, 510320, China. Electronic address: [email protected].
⁸ Department of Chemistry, College of Science, Academy for Advanced Interdisciplinary Studies, and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen, Guangdong, 518000, China. Electronic address: [email protected].
⁹ Department of Chemistry, College of Science, Academy for Advanced Interdisciplinary Studies, and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen, Guangdong, 518000, China. Electronic address: [email protected].

Abstract

S-217622 (Ensitrelvir) is a reversible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3-chymotrypsin-like protease (3CL^pro) inhibitor which obtained emergency regulatory approval in Japan for the treatment of SARS-CoV-2 infection on Nov 22, 2022. Herein, analogs of S-271622 with deuterium-for-hydrogen replacement were synthesized for comparison of the antiviral activities and pharmacokinetic (PK) profiles. Compared to the parent compound, C11-d2-S-217622 compound YY-278 retained in vitro activity against 3CL^pro and SARS-CoV-2. X-ray crystal structural studies showed similar interactions of SARS-CoV-2 3CL^pro with YY-278 and S-271622. The PK profiling revealed the relatively favorable bioavailability and plasma exposure of YY-278. In addition, YY-278, as well as S-217622, displayed broadly anti-coronaviral activities against 6 other coronaviruses that infect humans and animals. These results laid the foundation for further research on the therapeutic potential of YY-278 against COVID-19 and other coronaviral diseases.

Keywords: 3-chymotrypsin-like protease; Coronavirus; Crystal structure; Deuterated drug; S-217622 (ensitrelvir); SARS-CoV-2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antiviral Agents / therapeutic use
COVID-19*
Humans
Japan
Protease Inhibitors / chemistry
SARS-CoV-2*

Substances

Antiviral Agents
ensitrelvir
Protease Inhibitors