Ginkgolic acids inhibit SARS-CoV-2 and its variants by blocking the spike protein/ACE2 interplay

  • Int J Biol Macromol. 2023 Jan 31:226:780-792. doi: 10.1016/j.ijbiomac.2022.12.057.
Yusen Xiang  1 ,  Guanglei Zhai  2 ,  Yaozong Li  3 ,  Mengge Wang  1 ,  Xixiang Chen  4 ,  Ruyu Wang  1 ,  Hang Xie  5 ,  Weidong Zhang  6 ,  Guangbo Ge  1 ,  Qian Zhang  7 ,  Yechun Xu  8 ,  Amedeo Caflisch  9 ,  Jianrong Xu  10 ,  Hongzhuan Chen  11 ,  Lili Chen  12
Affiliations
  • 1. Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 2. Shanghai HighsLab Therapeutics. Inc., Shanghai 201203, China.
  • 3. Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland; Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
  • 4. Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China.
  • 5. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 6. Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai Institute of Infectious Diseases and Biosafety, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 7. Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 8. CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 9. Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
  • 10. Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China; Shanghai Universities Collaborative Innovation Center for Translational Medicine, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China. Electronic address: [email protected].
  • 11. Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: [email protected].
  • 12. Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: [email protected].
PMID: 36521705 DOI: 10.1016/j.ijbiomac.2022.12.057
Abstract

Targeting the interaction between the spike protein receptor binding domain (S-RBD) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and angiotensin-converting enzyme 2 (ACE2) is a potential therapeutic strategy for treating coronavirus disease 2019 (COVID-19). However, we still lack small-molecule drug candidates for this target due to the missing knowledge in the hot spots for the protein-protein interaction. Here, we used NanoBiT technology to identify three Ginkgolic acids from an in-house traditional Chinese medicine (TCM) library, and they interfere with the S-RBD/ACE2 interplay. Our pseudovirus assay showed that one of the compounds, Ginkgolic acid C17:1 (GA171), significantly inhibits the entry of original SARS-CoV-2 and its variants into the ACE2-overexpressed HEK293T cells. We investigated and proposed the binding sites of GA171 on S-RBD by combining molecular docking and molecular dynamics simulations. Site-directed mutagenesis and surface plasmon resonance revealed that GA171 specifically binds to the pocket near R403 and Y505, critical residues of S-RBD for S-RBD interacting with ACE2. Thus, we provide structural insights into developing new small-molecule inhibitors and vaccines against the proposed S-RBD binding site.

Keywords
Ginkgolic acid; S-RBD; SARS-CoV-2.
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