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Discovery of 9,10-dihydrophenanthrene derivatives as SARS-CoV-2 3CLpro inhibitors for treating COVID-19.
Zhang, Jian-Wei; Xiong, Yuan; Wang, Feng; Zhang, Fu-Mao; Yang, Xiaodi; Lin, Guo-Qiang; Tian, Ping; Ge, Guangbo; Gao, Dingding.
  • Zhang JW; Shanghai Frontiers Science Center of TCM Chemical Biology, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • Xiong Y; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • Wang F; Shanghai Frontiers Science Center of TCM Chemical Biology, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • Zhang FM; Shanghai Frontiers Science Center of TCM Chemical Biology, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • Yang X; Shanghai Frontiers Science Center of TCM Chemical Biology, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • Lin GQ; Shanghai Frontiers Science Center of TCM Chemical Biology, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • Tian P; Shanghai Frontiers Science Center of TCM Chemical Biology, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: tianping@shutcm.edu.cn.
  • Ge G; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: geguangbo@dicp.ac.cn.
  • Gao D; Shanghai Frontiers Science Center of TCM Chemical Biology, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: gaodingding@shutcm.edu.cn.
Eur J Med Chem ; 228: 114030, 2022 Jan 15.
Article in English | MEDLINE | ID: covidwho-1768048
ABSTRACT
The epidemic coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now spread worldwide and efficacious therapeutics are urgently needed. 3-Chymotrypsin-like cysteine protease (3CLpro) is an indispensable protein in viral replication and represents an attractive drug target for fighting COVID-19. Herein, we report the discovery of 9,10-dihydrophenanthrene derivatives as non-peptidomimetic and non-covalent inhibitors of the SARS-CoV-2 3CLpro. The structure-activity relationships of 9,10-dihydrophenanthrenes as SARS-CoV-2 3CLpro inhibitors have carefully been investigated and discussed in this study. Among all tested 9,10-dihydrophenanthrene derivatives, C1 and C2 display the most potent SARS-CoV-2 3CLpro inhibition activity, with IC50 values of 1.55 ± 0.21 µM and 1.81 ± 0.17 µM, respectively. Further enzyme kinetics assays show that these two compounds dose-dependently inhibit SARS-CoV-2 3CLprovia a mixed-inhibition manner. Molecular docking simulations reveal the binding modes of C1 in the dimer interface and substrate-binding pocket of the target. In addition, C1 shows outstanding metabolic stability in the gastrointestinal tract, human plasma, and human liver microsome, suggesting that this agent has the potential to be developed as an orally administrated SARS-CoV-2 3CLpro inhibitor.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Drug Discovery / Coronavirus 3C Proteases / COVID-19 Drug Treatment Type of study: Prognostic study Topics: Traditional medicine Limits: Humans Language: English Journal: Eur J Med Chem Year: 2022 Document Type: Article Affiliation country: J.ejmech.2021.114030

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Drug Discovery / Coronavirus 3C Proteases / COVID-19 Drug Treatment Type of study: Prognostic study Topics: Traditional medicine Limits: Humans Language: English Journal: Eur J Med Chem Year: 2022 Document Type: Article Affiliation country: J.ejmech.2021.114030