Discovery of New Fusion Inhibitor Peptides against SARS-CoV-2 by Targeting the Spike S2 Subunit

• Published in: Biomolecules & therapeutics Vol. 29; no. 3; pp. 282 - 289
• Main Authors: Kandeel, Mahmoud, Yamamoto, Mizuki, Tani, Hideki, Kobayashi, Ayako, Gohda, Jin, Kawaguchi, Yasushi, Park, Byoung Kwon, Kwon, Hyung-Joo, Inoue, Jun-ichiro, Alkattan, Abdallah
• Format: Journal Article
• Language: English
• Published: Korea (South) The Korean Society of Applied Pharmacology 01.05.2021; 한국응용약물학회
• Subjects: Original; 약학; COVID-19; SARS-CoV-2; Fusion inhibitors; Antiviral drugs
• ISSN: 1976-9148; 2005-4483
• DOI: 10.4062/biomolther.2020.201

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.