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Identification of Vitamin K3 and its analogues as covalent inhibitors of SARS-CoV-2 3CLpro.
Wang, Ruyu; Hu, Qing; Wang, Haonan; Zhu, Guanghao; Wang, Mengge; Zhang, Qian; Zhao, Yishu; Li, Chunyu; Zhang, Yani; Ge, Guangbo; Chen, Hongzhuan; Chen, Lili.
  • Wang R; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • Hu Q; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • Wang H; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • Zhu G; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • Wang M; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • Zhang Q; Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
  • Zhao Y; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • Li C; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • Zhang Y; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • Ge G; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: geguangbo@dicp.ac.cn.
  • Chen H; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: yaoli@shsmu.edu.cn.
  • Chen L; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: llchen@shutcm.edu.cn.
Int J Biol Macromol ; 183: 182-192, 2021 Jul 31.
Article in English | MEDLINE | ID: covidwho-1305238
ABSTRACT
After the emergence of the pandemic, repurposed drugs have been considered as a quicker way of finding potential antiviral agents. SARS-CoV-2 3CLpro is essential for processing the viral polyproteins into mature non-structural proteins, making it an attractive target for developing antiviral agents. Here we show that Vitamin K3 screened from the FDA-Approved Drug Library containing an array of 1,018 compounds has potent inhibitory activity against SARS-CoV-2 3CLpro with the IC50 value of 4.78 ± 1.03 µM, rather than Vitamin K1, K2 and K4. Next, the time-dependent inhibitory experiment was carried out to confirm that Vitamin K3 could form the covalent bond with SARS-CoV-2 3CLpro. Then we analyzed the structure-activity relationship of Vitamin K3 analogues and identified 5,8-dihydroxy-1,4-naphthoquinone with 9.8 times higher inhibitory activity than Vitamin K3. Further mass spectrometric analysis and molecular docking study verified the covalent binding between Vitamin K3 or 5,8-dihydroxy-1,4-naphthoquinone and SARS-CoV-2 3CLpro. Thus, our findings provide valuable information for further optimization and design of novel inhibitors based on Vitamin K3 and its analogues, which may have the potential to fight against SARS-CoV-2.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Cysteine Proteinase Inhibitors / Vitamin K 3 / Coronavirus 3C Proteases / SARS-CoV-2 Limits: Humans Language: English Journal: Int J Biol Macromol Year: 2021 Document Type: Article Affiliation country: J.ijbiomac.2021.04.129

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Cysteine Proteinase Inhibitors / Vitamin K 3 / Coronavirus 3C Proteases / SARS-CoV-2 Limits: Humans Language: English Journal: Int J Biol Macromol Year: 2021 Document Type: Article Affiliation country: J.ijbiomac.2021.04.129