Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Discovery of New Fusion Inhibitor Peptides against SARS-CoV-2 by Targeting the Spike S2 Subunit

  • Kandeel, Mahmoud (Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University) ;
  • Yamamoto, Mizuki (Research Center for Asian Infectious Diseases, Institute of Medical Science, The University of Tokyo) ;
  • Tani, Hideki (Department of Virology, Toyama Institute of Health) ;
  • Kobayashi, Ayako (Research Center for Asian Infectious Diseases, Institute of Medical Science, The University of Tokyo) ;
  • Gohda, Jin (Research Center for Asian Infectious Diseases, Institute of Medical Science, The University of Tokyo) ;
  • Kawaguchi, Yasushi (Research Center for Asian Infectious Diseases, Institute of Medical Science, The University of Tokyo) ;
  • Park, Byoung Kwon (Department of Microbiology, Hallym University College of Medicine) ;
  • Kwon, Hyung-Joo (Department of Microbiology, Hallym University College of Medicine) ;
  • Inoue, Jun-ichiro (The University of Tokyo) ;
  • Alkattan, Abdallah (Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University)
  • Received : 2020.11.06
  • Accepted : 2020.12.10
  • Published : 2021.05.01
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Abstract

A novel coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), caused a worldwide pandemic. Our aim in this study is to produce new fusion inhibitors against SARS-CoV-2, which can be the basis for developing new antiviral drugs. The fusion core comprising the heptad repeat domains (HR1 and HR2) of SARS-CoV-2 spike (S) were used to design the peptides. A total of twelve peptides were generated, comprising a short or truncated 24-mer (peptide #1), a long 36-mer peptide (peptide #2), and ten peptide #2 analogs. In contrast to SARS-CoV, SARS-CoV-2 S-mediated cell-cell fusion cannot be inhibited with a minimal length, 24-mer peptide. Peptide #2 demonstrated potent inhibition of SARS-CoV-2 S-mediated cell-cell fusion at 1 µM concentration. Three peptide #2 analogs showed IC50 values in the low micromolar range (4.7-9.8 µM). Peptide #2 inhibited the SARS-CoV-2 pseudovirus assay at IC50=1.49 µM. Given their potent inhibition of viral activity and safety and lack of cytotoxicity, these peptides provide an attractive avenue for the development of new prophylactic and therapeutic agents against SARS-CoV-2.

Keywords

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