2. Academic Validation
  3. Development of novel antivrial agents that induce the degradation of the main protease of human-infecting coronaviruses

Development of novel antivrial agents that induce the degradation of the main protease of human-infecting coronaviruses

  • Eur J Med Chem. 2024 Sep 5:275:116629. doi: 10.1016/j.ejmech.2024.116629.
Shuihong Cheng 1,  Yong Feng 2,  Wei Li 3,  Tong Liu 4,  Xun Lv 4,  Xiaomei Tong 2,  Gan Xi 4,  Xin Ye 2,  Xuebing Li 5
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Chaoyang District, Beijing, 100101, China; Savaid Medical School, University of Chinese Academy of Sciences, Huairou District, Beijing, 101408, China. Electronic address: csh_04@163.com.
  • 2 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Chaoyang District, Beijing, 100101, China.
  • 3 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, 100101, China.
  • 4 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Chaoyang District, Beijing, 100101, China; Savaid Medical School, University of Chinese Academy of Sciences, Huairou District, Beijing, 101408, China.
  • 5 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Chaoyang District, Beijing, 100101, China; Savaid Medical School, University of Chinese Academy of Sciences, Huairou District, Beijing, 101408, China. Electronic address: lixb@im.ac.cn.
PMID: 38941718 DOI: 10.1016/j.ejmech.2024.116629
Abstract

The family of human-infecting coronaviruses (HCoVs) poses a serious threat to global health and includes several highly pathogenic strains that cause severe respiratory illnesses. It is essential that we develop effective broad-spectrum anti-HCoV agents to prepare for future outbreaks. In this study, we used PROteolysis TArgeting Chimera (PROTAC) technology focused on degradation of the HCoV main protease (Mpro), a conserved Enzyme essential for viral replication and pathogenicity. By adapting the Mpro inhibitor GC376, we produced two novel PROTACs, P2 and P3, which showed relatively broad-spectrum activity against the human-infecting CoVs HCoV-229E, HCoV-OC43, and SARS-CoV-2. The concentrations of these PROTACs that reduced virus replication by 50 % ranged from 0.71 to 4.6 μM, and neither showed cytotoxicity at 100 μM. Furthermore, mechanistic binding studies demonstrated that P2 and P3 effectively targeted HCoV-229E, HCoV-OC43, and SARS-CoV-2 by degrading Mpro within cells in vitro. This study highlights the potential of PROTAC technology in the development of broad-spectrum anti-HCoVs agents, presenting a novel approach for dealing with future viral outbreaks, particularly those stemming from CoVs.

Keywords

Broad-spectrum; Degradation; Main protease; PROTAC; anti-HCoV agents.

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