A new generation M^(pro)inhibitor with potent activity against SARS-CoV-2 Omicron variants  

作　　者：Chong Huang Huiping Shuai Jingxin Qiao Yuxin Hou Rui Zeng Anjie Xia Lingwan Xie Zhen Fang Yueyue Li Chaemin Yoon Qiao Huang Bingjie Hu Jing You Baoxue Quan Xiu Zhao Nihong Guo Shiyu Zhang Ronggang Ma Jiahao Zhang Yifei Wang Ruicheng Yang Shanshan Zhang Jinshan Nan Haixing Xu Falu Wang Jian Lei Hin Chu Shengyong Yang 

机构地区：[1]State Key Laboratory of Biotherapy and Cancer Center and National Clinical Research Center for Geriatrics,West China Hospital,Sichuan University,Chengdu,Sichuan 610041,China [2]State Key Laboratory of Emerging Infectious Diseases,Li Ka Shing Faculty of Medicine,The University of Hong Kong,Pokfulam,Hong Kong Special Administrative Region,China [3]Department of Microbiology,Li Ka Shing Faculty of Medicine,The University of Hong Kong,Pokfulam,Hong Kong Special Administrative Region,China [4]Key Laboratory of Drug Targeting and Drug Delivery Systems,Ministry of Education,West China School of Pharmacy,Sichuan University,Chengdu,Sichuan 610041,China

出　　处：《Signal Transduction and Targeted Therapy》2023年第4期1970-1982,共13页信号转导与靶向治疗（英文）

基　　金：National Natural Science Foundation of China[82130104,81930125,T2221004(S.Y.);22107081(B.Q.)],National Key R&D Program of China[2022YFC2303701 and 2021YFF0702004(J.L.)],1.3.5 project for disciplines of excellence;West China Hospital,Sichuan University[ZYXY21001(S.Y.);ZYYC21008(J.L.)],the fast-track grants of SARS-CoV-2 research,West China Hospital,Sichuan University[HX-2019-nCoV-053(S.Y.)];National Clinical Research Center for Geriatrics,West China Hospital,Sichuan University[Z2021JC008(J.L.)];National Natural Science Foundation of China Excellent Young Scientists Fund(Hong Kong and Macao)[32122001(H.C.)];the Health and Medical Research Fund[CID-HKU1-5,COVID1903010-14,and 20190652(H.C.)];the Food and Health Bureau,The Government of the Hong Kong Special Administrative Region;the General Research Fund[17118621,17123920 and 17119122(H.C.)]of Research Grants Council,the Government of the Hong Kong Special Administrative Region;the National Program on Key Research Project of China[2020YFA0707500 and 2020YFA0707504(H.C.)].

摘　　要：Emerging SARS-CoV-2 variants, particularly the Omicron variant and its sublineages, continually threaten the global public health.Small molecule antivirals are an effective treatment strategy to fight against the virus. However, the first-generation antivirals eithershow limited clinical efficacy and/or have some defects in pharmacokinetic (PK) properties. Moreover, with increased use of thesedrugs across the globe, they face great pressure of drug resistance. We herein present the discovery and characterization of a newgeneration antiviral drug candidate (SY110), which is a potent and selective inhibitor of SARS-CoV-2 main protease (Mpro). Thiscompound displayed potent in vitro antiviral activity against not only the predominant SARS-CoV-2 Omicron sublineage BA.5, butalso other highly pathogenic human coronaviruses including SARS-CoV-1 and MERS-CoV. In the Omicron-infected K18-hACE2mouse model, oral treatment with SY110 significantly lowered the viral burdens in lung and alleviated the virus-induced pathology.Importantly, SY110 possesses favorable PK properties with high oral drug exposure and oral bioavailability, and also an outstandingsafety profile. Furthermore, SY110 exhibited sensitivity to several drug-resistance Mpro mutations. Collectively, this investigationprovides a promising new drug candidate against Omicron and other variants of SARS-CoV-2.

关 键 词：treatment predominant POTENT 

分 类 号：R563.1[医药卫生—呼吸系统]