Structure-based design of pan-coronavirus inhibitors targeting host cathepsin L and calpain-1
文献类型：期刊论文
| 作者 | Xie, Xiong8,9; Lan, Qiaoshuai7; Zhao, Jinyi5,6,8; Zhang, Sulin8,9; Liu, Lu5,6,8,9; Zhang, Yumin4; Xu, Wei7; Shao, Maolin5,6,8; Peng, Jingjing8,9; Xia, Shuai7 |
| 刊名 | SIGNAL TRANSDUCTION AND TARGETED THERAPY
 |
| 出版日期 | 2024-03-06 |
| 卷号 | 9期号:1页码:14 |
| ISSN号 | 2095-9907 |
| DOI | 10.1038/s41392-024-01758-8 |
| 通讯作者 | Zhang, Leike(zhangleike@wh.iov.cn) ; Bai, Fang(baifang@shanghaitech.edu.cn) ; Zhao, Yao(zhaoyao@shanghaitech.edu.cn) ; Jiang, Shibo(shibojiang@fudan.edu.cn) ; Liu, Hong(hliu@simm.ac.cn) |
| 英文摘要 | 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 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 alpha-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 alpha-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. |
| WOS关键词 | PROTEASE INHIBITOR ; PROCATHEPSIN-L ; L REVEALS ; MECHANISMS ; DISCOVERY |
| 资助项目 | National Natural Science Foundation of China (National Science Foundation of China) ; Shanghai Synchrotron Radiation Facility ; ShanghaiTech High-Performance Computing Platform ; Discovery Technology Platform of Shanghai Institute for Advanced Immunochemical Studies (SIAIS) at ShanghaiTech University[82130105] ; Discovery Technology Platform of Shanghai Institute for Advanced Immunochemical Studies (SIAIS) at ShanghaiTech University[82121005] ; Discovery Technology Platform of Shanghai Institute for Advanced Immunochemical Studies (SIAIS) at ShanghaiTech University[92169112] ; Discovery Technology Platform of Shanghai Institute for Advanced Immunochemical Studies (SIAIS) at ShanghaiTech University[82041036] ; Discovery Technology Platform of Shanghai Institute for Advanced Immunochemical Studies (SIAIS) at ShanghaiTech University[T2225002] ; Discovery Technology Platform of Shanghai Institute for Advanced Immunochemical Studies (SIAIS) at ShanghaiTech University[82002142] ; Discovery Technology Platform of Shanghai Institute for Advanced Immunochemical Studies (SIAIS) at ShanghaiTech University[82341093] ; Discovery Technology Platform of Shanghai Institute for Advanced Immunochemical Studies (SIAIS) at ShanghaiTech University[32200131] ; National Natural Science Foundation of China[2021YFC2300703] ; National Program on Key Research Project of China[2022YFC0868900] ; National Program on Key Research Project of China[2021YFC0864900] ; National Program on Key Research Project of China[2021YFC2300700] ; National Key R&D Program of China[20QA1406400] ; National Key R&D Program of China[LG202101-01-07] ; National Key R&D Program of China[LG202103-04-03] ; Shanghai Municipal Science and Technology Major Project, Shanghai Science and Technology Development Funds[2023296] ; Youth Innovation Promotion Association CAS[YDZX20213100001556] ; Science and Technology Commission of Shanghai Municipality |
| WOS研究方向 | Biochemistry & Molecular Biology ; Cell Biology |
| 语种 | 英语 |
| 出版者 | SPRINGERNATURE |
| WOS记录号 | WOS:001179090700001 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/310136]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Zhang, Leike; Bai, Fang; Zhao, Yao; Jiang, Shibo; Liu, Hong |
| 作者单位 | 1.Shenzhen Third Peoples Hosp, Natl Clin Res Ctr Infect Dis, Shenzhen 518112, Peoples R China 2.UCAS, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, 138 Xian Lin Rd, Nanjing 210023, Jiangsu, Peoples R China 4.Chinese Acad Sci, Wuhan Inst Virol, Ctr Biosafety Mega Sci, State Key Lab Virol, Wuhan 430071, Peoples R China 5.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 6.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 201210, Peoples R China 7.Fudan Univ, Shanghai Inst Infect Dis & Biosecur, Sch Basic Med Sci, Key Lab Med Mol Virol,MOE,NHC,CAMS, Shanghai 200032, Peoples R China 8.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 9.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res,CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Xie, Xiong,Lan, Qiaoshuai,Zhao, Jinyi,et al. Structure-based design of pan-coronavirus inhibitors targeting host cathepsin L and calpain-1[J]. SIGNAL TRANSDUCTION AND TARGETED THERAPY,2024,9(1):14. |
| APA | Xie, Xiong.,Lan, Qiaoshuai.,Zhao, Jinyi.,Zhang, Sulin.,Liu, Lu.,...&Liu, Hong.(2024).Structure-based design of pan-coronavirus inhibitors targeting host cathepsin L and calpain-1.SIGNAL TRANSDUCTION AND TARGETED THERAPY,9(1),14. |
| MLA | Xie, Xiong,et al."Structure-based design of pan-coronavirus inhibitors targeting host cathepsin L and calpain-1".SIGNAL TRANSDUCTION AND TARGETED THERAPY 9.1(2024):14. |
入库方式： OAI收割
来源：上海药物研究所
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