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Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease.
Dai, Wenhao; Zhang, Bing; Jiang, Xia-Ming; Su, Haixia; Li, Jian; Zhao, Yao; Xie, Xiong; Jin, Zhenming; Peng, Jingjing; Liu, Fengjiang; Li, Chunpu; Li, You; Bai, Fang; Wang, Haofeng; Cheng, Xi; Cen, Xiaobo; Hu, Shulei; Yang, Xiuna; Wang, Jiang; Liu, Xiang; Xiao, Gengfu; Jiang, Hualiang; Rao, Zihe; Zhang, Lei-Ke; Xu, Yechun; Yang, Haitao; Liu, Hong.
  • Dai W; State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Zhang B; School of Pharmacy, China Pharmaceutical University, Nanjing 210009, Jiangsu, China.
  • Jiang XM; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • Su H; State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, China.
  • Li J; State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Zhao Y; University of Chinese Academy of Sciences, Beijing 100049, China.
  • Xie X; State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Jin Z; College of Pharmacy, Nanjing University of Chinese Medicine, Qixia District, Nanjing 210023, China.
  • Peng J; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • Liu F; State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Li C; University of Chinese Academy of Sciences, Beijing 100049, China.
  • Li Y; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • Bai F; State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Wang H; University of Chinese Academy of Sciences, Beijing 100049, China.
  • Cheng X; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • Cen X; State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Hu S; University of Chinese Academy of Sciences, Beijing 100049, China.
  • Yang X; National Chengdu Center for Safety Evaluation of Drugs, Westchina Hospital of Sichuan University, High-Tech Development Zone, Chengdu, Sichuan 610041, China.
  • Wang J; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • Liu X; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • Xiao G; State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Jiang H; National Chengdu Center for Safety Evaluation of Drugs, Westchina Hospital of Sichuan University, High-Tech Development Zone, Chengdu, Sichuan 610041, China.
  • Rao Z; State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Zhang LK; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • Xu Y; State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Yang H; University of Chinese Academy of Sciences, Beijing 100049, China.
  • Liu H; State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Response, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300353, China.
Science ; 368(6497): 1331-1335, 2020 06 19.
Article in English | MEDLINE | ID: covidwho-108792
ABSTRACT
SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the etiological agent responsible for the global COVID-19 (coronavirus disease 2019) outbreak. The main protease of SARS-CoV-2, Mpro, is a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds (11a and 11b) targeting Mpro Both exhibited excellent inhibitory activity and potent anti-SARS-CoV-2 infection activity. The x-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a or 11b, both determined at a resolution of 1.5 angstroms, showed that the aldehyde groups of 11a and 11b are covalently bound to cysteine 145 of Mpro Both compounds showed good pharmacokinetic properties in vivo, and 11a also exhibited low toxicity, which suggests that these compounds are promising drug candidates.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Drug Design / Viral Nonstructural Proteins / Betacoronavirus Type of study: Etiology study / Experimental Studies / Prognostic study / Randomized controlled trials Topics: Traditional medicine Limits: Animals / Female / Humans / Male Language: English Journal: Science Year: 2020 Document Type: Article Affiliation country: Science.abb4489

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Drug Design / Viral Nonstructural Proteins / Betacoronavirus Type of study: Etiology study / Experimental Studies / Prognostic study / Randomized controlled trials Topics: Traditional medicine Limits: Animals / Female / Humans / Male Language: English Journal: Science Year: 2020 Document Type: Article Affiliation country: Science.abb4489