Novel nucleocapsid protein-targeting phenanthridine inhibitors of SARS-CoV-2

  • Eur J Med Chem. 2022 Jan 5;227:113966. doi: 10.1016/j.ejmech.2021.113966.
Yi-Ting Wang  1 ,  Xin-Yan Long  2 ,  Xiao Ding  1 ,  Shi-Rui Fan  1 ,  Jie-Yun Cai  1 ,  Bi-Juan Yang  1 ,  Xin-Fang Zhang  3 ,  Rong-Hua Luo  4 ,  Lian Yang  1 ,  Ting Ruan  5 ,  Juan Ren  3 ,  Chen-Xu Jing  1 ,  Yong-Tang Zheng  6 ,  Xiao-Jiang Hao  7 ,  Duo-Zhi Chen  8
Affiliations
  • 1. State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, PR China.
  • 2. 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 Chinese Academy of Sciences, Kunming, Yunnan, 650204, PR China.
  • 3. 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.
  • 4. 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.
  • 5. 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.
  • 6. 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: [email protected].
  • 7. 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: [email protected].
  • 8. 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: [email protected].
PMID: 34749200 DOI: 10.1016/j.ejmech.2021.113966
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.

Keywords
N-terminal domain; Nucleocapsid protein; Phenanthridine; SARS-CoV-2.
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