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

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

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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 efficacy 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 α-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 α-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 EC50 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 anti-inflammatory 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.

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

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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

University of Chinese Academy of Sciences,Beijing 100049,China

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

Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology,ShanghaiTech University,Shanghai 201210,China

State Key Laboratory of Virology,Wuhan Institute of Viroiogy,Center for Biosafety Mega-Science,Chinese Academy of Sciences,Wuhan 430071,China

School of Chinese Materia Medica,Nanjing University of Chinese Medicine,138 Xian Lin Road,Jiangsu 210023 Nanjing,China

School of Pharmaceutical Science and Technology,Hangzhou Institute for Advanced Study,UCAS,Hangzhou 310024,China

National Clinical Research Center for Infectious Disease,Shenzhen Third People's Hospital,Shenzhen 518112,China

School of Chinese Materia Medica,Nanjing University of Chinese Medicine,138 Xian Lin Road,Jiangsu 210023 Nan

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国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金National Program on Key Research Project of China国家重点研发计划国家重点研发计划国家重点研发计划Shanghai Municipal Science and Technology Major Project,Shanghai Science and Technology Development FundsLingang LaboratoryLingang Laboratory中国科学院青年创新促进会项目上海市科委项目

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2024

10.1038/s41392-024-01758-8

信号转导与靶向治疗(英文)

信号转导与靶向治疗(英文)

CSTPCD
ISSN：
年,卷(期)：2024.9(4)
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