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Repurposing of HIV/HCV protease inhibitors against SARS-CoV-2 3CLpro.
Ma, Ling; Li, Quanjie; Xie, Yongli; Yi, Dongrong; Guo, Saisai; Guo, Fei; Wang, Jing; Yang, Long; Cen, Shan.
  • Ma L; Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China.
  • Li Q; Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China.
  • Xie Y; Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China.
  • Jianyuan Zhao; Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China.
  • Yi D; Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China.
  • Guo S; Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China.
  • Guo F; Institute of Pathogen Biology, Chinese Academy of Medical Science, Beijing, China.
  • Wang J; Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China. Electronic address: jingwang@imb.pumc.edu.cn.
  • Yang L; School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China. Electronic address: longyangrich@hotmail.com.
  • Cen S; Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China. Electronic address: shancen@imb.pumc.edu.cn.
Antiviral Res ; 207: 105419, 2022 11.
Article in English | MEDLINE | ID: covidwho-2041573
ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen that caused the global COVID-19 outbreak. The 3C-like protease (3CLpro) of SARS-CoV-2 plays a key role in virus replication and has become an ideal target for antiviral drug design. In this work, we have employed bioluminescence resonance energy transfer (BRET) technology to establish a cell-based assay for screening inhibitors against SARS-CoV-2 3CLpro, and then applied the assay to screen a collection of known HIV/HCV protease inhibitors. Our results showed that the assay is capable of quantification of the cleavage efficiency of 3CLpro with good reproducibility (Z' factor is 0.59). Using the assay, we found that 9 of 26 protease inhibitors effectively inhibited the activity of SARS-CoV-2 3CLpro in a dose-dependent manner. Among them, four compounds exhibited the ability to bind to 3CLproin vitro. HCV protease inhibitor simeprevir showed the most potency against 3CLpro with an EC50 vale of 2.6 µM, bound to the active site pocket of 3CLpro in a predicted model, and importantly, exhibited a similar activity against the protease containing the mutations P132H in Omicron variants. Taken together, this work demonstrates the feasibility of using the cell-based BRET assay for screening 3CLpro inhibitors and supports the potential of simeprevir for the development of 3CLpro inhibitors.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: HIV Infections / Hepatitis C / HIV Protease Inhibitors / COVID-19 Drug Treatment Type of study: Prognostic study Topics: Variants Limits: Humans Language: English Journal: Antiviral Res Year: 2022 Document Type: Article Affiliation country: J.antiviral.2022.105419

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Full text: Available Collection: International databases Database: MEDLINE Main subject: HIV Infections / Hepatitis C / HIV Protease Inhibitors / COVID-19 Drug Treatment Type of study: Prognostic study Topics: Variants Limits: Humans Language: English Journal: Antiviral Res Year: 2022 Document Type: Article Affiliation country: J.antiviral.2022.105419