Structure-based design of pan-coronavirus inhibitors targeting host cathepsin L and calpain-1  

作　　者：Xiong Xie Qiaoshuai Lan Jinyi Zhao Sulin Zhang Lu Liu Yumin Zhang Wei Xu Maolin Shao Jingjing Peng Shuai Xia Yan Zhu Keke Zhang Xianglei Zhang Ruxue Zhang jian Li Wenhao Dai Zhen Ge Shulei Hu Changyue Yu Jiang Wang Dakota Ma Mingyue Zheng Haitao Yang Gengfu Xiao Zihe Rao Lu Lu Leike Zhang Fang Bai Yao Zhao Shibo Jiang Hong Liu 

机构地区：[1]Drug Discovery and Design Center,State Key Laboratory of Drug Research,CAS Key Laboratory of Receptor Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [2]University of Chinese Academy of Sciences,Beijing 100049,China [3]Key Laboratory of Medical Molecular Virology(MOE/NHC/CAMS),School of Basic Medical Sciences,Shanghai Institute of Infectious Disease and Biosecurity,Fudan University,Shanghai 200032,China [4]Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology,ShanghaiTech University,Shanghai 201210,China [5]State Key Laboratory of Virology,Wuhan Institute of Virology,Center for Biosafety Mega-Science,Chinese Academy of Sciences,Wuhan 430071,China [6]School of Chinese Materia Medica,Nanjing University of Chinese Medicine,138 Xian Lin Road,Jiangsu 210023 Nanjing,China [7]School of Pharmaceutical Science and Technology,Hangzhou Institute for Advanced Study,UCAS,Hangzhou 310024,China [8]National Clinical Research Center for Infectious Disease,Shenzhen Third People's Hospital,Shenzhen 518112,China

出　　处：《Signal Transduction and Targeted Therapy》2024年第4期1651-1664,共14页信号转导与靶向治疗（英文）

基　　金：supported by the National Natural Science Foundation of China (Nos.82130105 to H.L.,82121005 to H.L.,92169112 to S.J.,82041036 to L.L.,T2225002 to M.Z.,82002142 to S.X.,82341093 to F.B.,and 32200131 to Y.Z.);the National Program on Key Research Project of China (2021YFC2300703 to L.L.);National Key R&D Program of China (2022YFC0868900 and 2021YFC0864900 to H.L.,2021YFC2300700 to L.Z.);Shanghai Municipal Science and Technology Major Project,Shanghai Science and Technology Development Funds (20QA1406400 to F.B.);Lingang Laboratory (LG202101-01-07 to H.Y.,LG202103-04-03 to W.D.);Youth Innovation Promotion Association CAS (2023296 to S.Z);the Science and Technology Commission of Shanghai Municipality (YDZX20213100001556 to H.Y.).

摘　　要：Respiratory disease caused by coronavirus infection remains a global health crisis.Although several SARS-CoV-2-specific vaccines and direct-acting antivirals are available,their effcacy on emerging coronaviruses in the future,including SARS-CoV-2 variants,might be compromised.Host-targeting antivirals provide preventive and therapeutic strategies to overcome resistance and manage future outbreak of emerging coronaviruses.Cathepsin L(CTSL)and calpain-1(CAPN1)are host cysteine proteases which play crucial roles in coronaviral entrance into cells and infection-related immune response.Here,two peptidomimetic a-ketoamide compounds,14a and 14b,were identified as potent dual target inhibitors against CTSL and CAPN1.The X-ray crystal structures of human CTSL and CAPN1 in complex with 14a and 14b revealed the covalent binding of a-ketoamide groups of 14a and 14b to C25 of CTSL and C115 of CAPN1.Both showed potent and broad-spectrum anticoronaviral activities in vitro,and it is worth noting that they exhibited low nanomolar potency against SARS-CoV-2 and its variants of concern(VOCs)with ECso values ranging from 0.80 to 161.7 nM in various cells.Preliminary mechanistic exploration indicated that they exhibited anticoronaviral activity through blocking viral entrance.Moreover,14a and 14b exhibited good oral pharmacokinetic properties in mice,rats and dogs,and favorable safety in mice.In addition,both 14a and 14b treatments demonstrated potent antiviral potency against SARS-CoV-2 XBB 1.16 variant infection in a K18-hACE2 transgenic mouse model.And 14b also showed effective antiviral activity against HCoV-OC43 infection in a mouse model with a final survival rate of 60%.Further evaluation showed that 14a and 14b exhibited excellent antiinflammatory effects in Raw 264.7 mouse macrophages and in mice with acute pneumonia.Taken together,these results suggested that 14a and 14b are promising drug candidates,providing novel insight into developing pan-coronavirus inhibitors with antiviral and anti-inflammatory properties.

关 键 词：CALPAIN OVERCOME ENTRANCE 

分 类 号：R373[医药卫生—病原生物学]