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 viru...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.展开更多
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+7 种基金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 Regionthe General Research Fund[17118621,17123920 and 17119122(H.C.)]of Research Grants Council,the Government of the Hong Kong Special Administrative Regionthe National Program on Key Research Project of China[2020YFA0707500 and 2020YFA0707504(H.C.)].
文摘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.
