2. Academic Validation
  3. Identification of novel small-molecule inhibitors of SARS-CoV-2 by chemical genetics

Identification of novel small-molecule inhibitors of SARS-CoV-2 by chemical genetics

  • Acta Pharm Sin B. 2024 Sep;14(9):4028-4044. doi: 10.1016/j.apsb.2024.05.026.
Chris Chun-Yiu Chan 1,  Qian Guo 1,  Jasper Fuk-Woo Chan 1 2 3 4,  Kaiming Tang 1,  Jian-Piao Cai 1,  Kenn Ka-Heng Chik 1 3,  Yixin Huang 5,  Mei Dai 6,  Bo Qin 6,  Chon Phin Ong 5,  Allen Wing-Ho Chu 1 3,  Wan-Mui Chan 1,  Jonathan Daniel Ip 1,  Lei Wen 1 3,  Jessica Oi-Ling Tsang 1 3,  Tong-Yun Wang 1,  Yubin Xie 1,  Zhenzhi Qin 1,  Jianli Cao 1 3,  Zi-Wei Ye 5,  Hin Chu 1 2 3,  Kelvin Kai-Wang To 1 2 3,  Xing-Yi Ge 7,  Tao Ni 5,  Dong-Yan Jin 3 5,  Sheng Cui 6,  Kwok-Yung Yuen 1 2 3 4,  Shuofeng Yuan 1 2 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Pokfulam, Hong Kong SAR 999077, China.
  • 2 Department of Infectious Diseases and Microbiology, the University of Hong Kong-Shenzhen Hospital, Shenzhen 518000, China.
  • 3 Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong SAR 999077, China.
  • 4 Academician Workstation of Hainan Province, Hainan Medical University-the University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Haikou 571100, China.
  • 5 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Pokfulam, Hong Kong SAR 999077, China.
  • 6 NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China.
  • 7 College of Biology, Hunan Provincial Key Laboratory of Medical Virology, Hunan University, Changsha 410082, China.
PMID: 39309487 DOI: 10.1016/j.apsb.2024.05.026
Abstract

There are only eight approved small molecule Antiviral drugs for treating COVID-19. Among them, four are nucleotide analogues (remdesivir, JT001, molnupiravir, and azvudine), while the Other four are Protease Inhibitors (nirmatrelvir, ensitrelvir, leritrelvir, and simnotrelvir-ritonavir). Antiviral resistance, unfavourable drug‒drug interaction, and toxicity have been reported in previous studies. Thus there is a dearth of new treatment options for SARS-CoV-2. In this work, a three-tier cell-based screening was employed to identify novel compounds with anti-SARS-CoV-2 activity. One compound, designated 172, demonstrated broad-spectrum Antiviral activity against multiple human pathogenic coronaviruses and different SARS-CoV-2 variants of concern. Mechanistic studies validated by reverse genetics showed that compound 172 inhibits the 3-chymotrypsin-like protease (3CLpro) by binding to an allosteric site and reduces 3CLpro dimerization. A drug synergistic checkerboard assay demonstrated that compound 172 can achieve drug synergy with nirmatrelvir in vitro. In vivo studies confirmed the Antiviral activity of compound 172 in both Golden Syrian Hamsters and K18 humanized ACE2 mice. Overall, this study identified an alternative druggable site on the SARS-CoV-2 3CLpro, proposed a potential combination therapy with nirmatrelvir to reduce the risk of Antiviral resistance and shed light on the development of allosteric Protease Inhibitors for treating a range of coronavirus diseases.

Keywords

3CLpro inhibitor; Allosteric-site inhibitor; Animal models; Broad-spectrum antiviral treatment; Chemical genetics; High throughput screening; Reverse genetics; SARS-CoV-2.

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