Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2020.201
Discovery of New Fusion Inhibitor Peptides against SARS-CoV-2 by Targeting the Spike S2 Subunit
Mahmoud Kandeel1,2,*, Mizuki Yamamoto3, Hideki Tani4, Ayako Kobayashi3, Jin Gohda3, Yasushi Kawaguchi3,5, Byoung Kwon Park6, Hyung-Joo Kwon6,*, Jun-ichiro Inoue7,* and Abdallah Alkattan1
1Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia
2Department of Pharmacology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
3Research Center for Asian Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
4Department of Virology, Toyama Institute of Health, Toyama 939-0363, Japan
5Division of Molecular Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
6Department of Microbiology, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea
7Senior Professor Office, The University of Tokyo, Tokyo 108-8639, Japan
*E-mail: mkandeel@kfu.edu.sa (Kandeel M), hjookwon@hallym.ac.kr (Kwon HJ), jun-i@ims.u-tokyo.ac.jp (Inoue J)
Tel: +966-056-891-8734 (Kandeel M), +82-33-248-2635 (Kwon HJ), +81-3-6409-2476 (Inoue J)
Fax: +966-013-589-6617 (Kandeel M), +82-33-241-3640 (Kwon HJ), +81-3-6409-2477 (Inoue J)
Received: November 6, 2020; Revised: December 8, 2020; Accepted: December 10, 2020; Published online: January 11, 2021.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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 SARSCoV-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: SARS-CoV-2, COVID-19, Fusion inhibitors, Antiviral drugs


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