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Novel nucleocapsid protein-targeting phenanthridine inhibitors of SARS-CoV-2.
Wang, Yi-Ting; Long, Xin-Yan; Ding, Xiao; Fan, Shi-Rui; Cai, Jie-Yun; Yang, Bi-Juan; Zhang, Xin-Fang; Luo, Rong-Hua; Yang, Lian; Ruan, Ting; Ren, Juan; Jing, Chen-Xu; Zheng, Yong-Tang; Hao, Xiao-Jiang; Chen, Duo-Zhi.
  • Wang YT; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, PR China.
  • Long XY; Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, PR China; Kunming College of Life Science, University of Chines
  • Ding X; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, PR China.
  • Fan SR; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, PR China.
  • Cai JY; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, PR China.
  • Yang BJ; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, PR China.
  • Zhang XF; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, PR China; Department of Chemical Science and Engineering, Yunnan University, Kunming, Yunnan, 650091, PR China.
  • Luo RH; Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, PR China.
  • Yang L; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, PR China.
  • Ruan T; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, PR China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, 650204, PR China.
  • Ren J; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, PR China; Department of Chemical Science and Engineering, Yunnan University, Kunming, Yunnan, 650091, PR China.
  • Jing CX; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, PR China.
  • Zheng YT; Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, PR China. Electronic address: zhengyt@mail.kiz.ac.cn.
  • Hao XJ; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, PR China. Electronic address: haoxj@mail.kib.ac.cn.
  • Chen DZ; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, PR China. Electronic address: chenduozhi@mail.kib.ac.cn.
Eur J Med Chem ; 227: 113966, 2022 Jan 05.
Article in English | MEDLINE | ID: covidwho-1487705
ABSTRACT
The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unprecedented in human history. As a major structural protein, nucleocapsid protein (NPro) is critical to the replication of SARS-CoV-2. In this work, 17 NPro-targeting phenanthridine derivatives were rationally designed and synthesized, based on the crystal structure of NPro. Most of these compounds can interact with SARS-CoV-2 NPro tightly and inhibit the replication of SARS-CoV-2 in vitro. Compounds 12 and 16 exhibited the most potent anti-viral activities with 50% effective concentration values of 3.69 and 2.18 µM, respectively. Furthermore, site-directed mutagenesis of NPro and Surface Plasmon Resonance (SPR) assays revealed that 12 and 16 target N-terminal domain (NTD) of NPro by binding to Tyr109. This work found two potent anti-SARS-CoV-2 bioactive compounds and also indicated that SARS-CoV-2 NPro-NTD can be a target for new anti-virus agents.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Phenanthridines / Coronavirus Nucleocapsid Proteins / SARS-CoV-2 Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: Eur J Med Chem Year: 2022 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Phenanthridines / Coronavirus Nucleocapsid Proteins / SARS-CoV-2 Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: Eur J Med Chem Year: 2022 Document Type: Article