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Ginkgolic acids inhibit SARS-CoV-2 and its variants by blocking the spike protein/ACE2 interplay.
Xiang, Yusen; Zhai, Guanglei; Li, Yaozong; Wang, Mengge; Chen, Xixiang; Wang, Ruyu; Xie, Hang; Zhang, Weidong; Ge, Guangbo; Zhang, Qian; Xu, Yechun; Caflisch, Amedeo; Xu, Jianrong; Chen, Hongzhuan; Chen, Lili.
  • Xiang Y; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • Zhai G; Shanghai HighsLab Therapeutics. Inc., Shanghai 201203, China.
  • Li Y; Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland; Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
  • Wang M; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • Chen X; 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
  • Wang R; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • Xie H; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • Zhang W; 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 Me
  • Ge G; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • Zhang Q; Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
  • Xu Y; CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Caflisch A; Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
  • Xu J; 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 20002
  • Chen H; 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: yaoli@shsmu.edu.cn.
  • Chen L; 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: llchen@shutcm.edu.cn.
Int J Biol Macromol ; 226: 780-792, 2023 Jan 31.
Article in English | MEDLINE | ID: covidwho-2246439
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 C171 (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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Topics: Traditional medicine / Vaccines / Variants Limits: Humans Language: English Journal: Int J Biol Macromol Year: 2023 Document Type: Article Affiliation country: J.ijbiomac.2022.12.057

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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Topics: Traditional medicine / Vaccines / Variants Limits: Humans Language: English Journal: Int J Biol Macromol Year: 2023 Document Type: Article Affiliation country: J.ijbiomac.2022.12.057