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
Dear Editor,The unexpected outbreak of a novel human coronavirus infection has imposed great threat to public health.Thus far,this newly-identified virus has spread to 215 countries and territories,infected more than ...Dear Editor,The unexpected outbreak of a novel human coronavirus infection has imposed great threat to public health.Thus far,this newly-identified virus has spread to 215 countries and territories,infected more than 3.5 million people,and caused over 240,000 deaths worldwide.1 Although intensified countermeasures have been implemented globally to control the virus infection,the pandemic is still surging with a daily increase in infection case of over 65,000 ever since April 1st 2020.1 No prophylactic vaccines or clinical drugs are currently available to prevent or treat the disease,namely coronavirus disease 2019(COVID-19).展开更多
Dear Editor,The outbreak of the SARS-CoV-2 epidemic once again demonstrates that RNA viruses,through mutations,genetic recombination and cross-species transmission,can pose a serious threat to the health of people wor...Dear Editor,The outbreak of the SARS-CoV-2 epidemic once again demonstrates that RNA viruses,through mutations,genetic recombination and cross-species transmission,can pose a serious threat to the health of people worldwide.Even after the severe acute respiratory syndrome(SARS)and middle east respiratory syndrome(MERS)outbreaks,the world still initially lacked effective means to control the current coronavirus disease 2019(COVID-19)outbreak.We must work together to develop effective drugs to treat existing and future potential coronavirus infections to reduce their impact on the global health system and human life.Due to time constraints,the'conventional drug in new use#method has become the main method of treating SARS-CoV-2 infections.However,long-term drug development goals should include treatments that can produce broad-spectrum effects on different coronaviruses,and provide the means to alleviate disease symptoms and prevent death.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.
基金supported by the special research fund on COVID-19 of Sichuan Province(grant No.2020YFS0010)the special research fund on COVID-19 of West China Hospital Sichuan University(grant No.HX-2019-nCoV-004).
文摘Dear Editor,The unexpected outbreak of a novel human coronavirus infection has imposed great threat to public health.Thus far,this newly-identified virus has spread to 215 countries and territories,infected more than 3.5 million people,and caused over 240,000 deaths worldwide.1 Although intensified countermeasures have been implemented globally to control the virus infection,the pandemic is still surging with a daily increase in infection case of over 65,000 ever since April 1st 2020.1 No prophylactic vaccines or clinical drugs are currently available to prevent or treat the disease,namely coronavirus disease 2019(COVID-19).
基金This work was supported by the National Key Research and Development Program(No.2016YFC1303502)National Major Scientific and Technological Special Project for"Significant New Drugs Development(2018ZX09733001)+2 种基金1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University,the Special grant from China Postdoctoral Science Foundation(No.2020TQ0217)the Post-Doctor Research Project,West China Hospital,Sichuan University(No.2020HXBH173)Post-Doctor Research Project,Sichuan University(No.2021SCU12028).
文摘Dear Editor,The outbreak of the SARS-CoV-2 epidemic once again demonstrates that RNA viruses,through mutations,genetic recombination and cross-species transmission,can pose a serious threat to the health of people worldwide.Even after the severe acute respiratory syndrome(SARS)and middle east respiratory syndrome(MERS)outbreaks,the world still initially lacked effective means to control the current coronavirus disease 2019(COVID-19)outbreak.We must work together to develop effective drugs to treat existing and future potential coronavirus infections to reduce their impact on the global health system and human life.Due to time constraints,the'conventional drug in new use#method has become the main method of treating SARS-CoV-2 infections.However,long-term drug development goals should include treatments that can produce broad-spectrum effects on different coronaviruses,and provide the means to alleviate disease symptoms and prevent death.
