Ginkgolic acid and anacardic acid are specific covalent inhibitors of SARS-CoV-2 cysteine proteases

  • Cell Biosci. 2021 Feb 28;11(1):45. doi: 10.1186/s13578-021-00564-x.
Zinuo Chen   #  1 ,  Qinghua Cui   #  1  2  3 ,  Laura Cooper   #  4 ,  Pin Zhang  5 ,  Hyun Lee  6 ,  Zhaoyu Chen  1 ,  Yanyan Wang  1 ,  Xiaoyun Liu  2 ,  Lijun Rong  7 ,  Ruikun Du  8  9  10
Affiliations
  • 1. College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
  • 2. Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
  • 3. Qingdao Academy of Chinese Medicinal Sciences, Shandong University of Traditional Chinese Medicine, Qingdao, 266122, China.
  • 4. Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA.
  • 5. Chicago BioSolutions Inc, 2242 W Harrison Street, Chicago, Illinois, 60612, United States.
  • 6. Department of Pharmaceutical Sciences, Center for Biomolecular Sciences, College of Pharmacy, Biophysics Core at Research Resources Center, University of Illinois at Chicago, Chicago, IL, 60607, USA.
  • 7. Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA. [email protected].
  • 8. College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China. [email protected].
  • 9. Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China. [email protected].
  • 10. Qingdao Academy of Chinese Medicinal Sciences, Shandong University of Traditional Chinese Medicine, Qingdao, 266122, China. [email protected].
  • # Contributed equally.
PMID: 33640032 DOI: 10.1186/s13578-021-00564-x
Abstract

Background: In the urgent campaign to develop therapeutics against SARS-CoV-2, natural products have been an important source of new lead compounds.

Results: We herein identified two natural products, ginkgolic acid and anacardic acid, as inhibitors using a high-throughput screen targeting the SARS-CoV-2 papain-like protease (PLpro). Moreover, our study demonstrated that the two hit compounds are dual inhibitors targeting the SARS-CoV-2 3-chymotrypsin-like protease (3CLpro) in addition to PLpro. A mechanism of action study using enzyme kinetics further characterized the two compounds as irreversible inhibitors against both 3CLpro and PLpro. Significantly, both identified compounds inhibit SARS-CoV-2 replication in vitro at nontoxic concentrations.

Conclusions: Our finding provides two novel natural products as promising SARS-CoV-2 antivirals.

Keywords
Anacardic acid; Ginkgolic acid; Natural product; Papain‐like protease; SARS-CoV-2.
Products