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

TitleGinkgolic acids inhibit SARS-CoV-2 and its variants by blocking the spike protein/ACE2 interplay
Publication TypeJournal Article
Year of Publication2023
AuthorsXiang Y., Zhai G., Li Y., Wang M., Chen X., Wang R., Xie H., Zhang W., Ge G., Zhang Q., Xu Y., Caflisch A., Xu J., Chen H., Chen L.
JournalInternational Journal of Biological Macromolecules
Date Published2023 Jan 31
Type of ArticleResearch Article
KeywordsAngiotensin-Converting Enzyme 2, COVID-19, HEK293 Cells, Humans, Molecular Docking Simulation, Molecular Dynamics Simulation, Protein Binding, SARS-CoV-2, Spike Glycoprotein, Coronavirus

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.



Alternate JournalInt. J. Biol. Macromol.
PubMed ID36521705
PubMed Central IDPMC9743696