Discovery of New Potent anti-MERS CoV Fusion Inhibitors

Mahmoud Kandeel; Mizuki Yamamoto; Byoung Kwon Park; Abdulla Al-Taher; Aya Watanabe; Jin Gohda; Yasushi Kawaguchi; Kentaro Oh-Hashi; Hyung-Joo Kwon; Jun-Ichiro Inoue

doi:10.3389/fphar.2021.685161

Discovery of New Potent anti-MERS CoV Fusion Inhibitors

Front Pharmacol. 2021 Jun 2:12:685161. doi: 10.3389/fphar.2021.685161. eCollection 2021.

Authors

Mahmoud Kandeel^{1

2}, Mizuki Yamamoto^{3

4}, Byoung Kwon Park⁵, Abdulla Al-Taher¹, Aya Watanabe⁴, Jin Gohda³, Yasushi Kawaguchi^{3

6}, Kentaro Oh-Hashi⁷, Hyung-Joo Kwon⁵, Jun-Ichiro Inoue^{4

8}

Affiliations

¹ Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa, Saudi Arabia.
² Department of Pharmacology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh, Egypt.
³ Research Center for Asian Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁴ Division of Cellular and Molecular Biology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
⁵ Department of Microbiology, Hallym University College of Medicine, Chuncheon, South Korea.
⁶ Division of Molecular Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁷ Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Gifu, Japan.
⁸ Senior Professor Office, The University of Tokyo, Tokyo, Japan.

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV), capable of zoonotic transmission, has been associated with emerging viral pneumonia in humans. In this study, a set of highly potent peptides were designed to prevent MERS-CoV fusion through competition with heptad repeat domain 2 (HR2) at its HR1 binding site. We designed eleven peptides with stronger estimated HR1 binding affinities than the wild-type peptide to prevent viral fusion with the cell membrane. Eight peptides showed strong inhibition of spike-mediated MERS-CoV cell-cell fusion with IC50 values in the nanomolar range (0.25-2.3 µM). Peptides #4-6 inhibited 95-98.3% of MERS-CoV plaque formation. Notably, peptide four showed strong inhibition of MERS-CoV plaques formation with EC50 = 0.302 µM. All peptides demonstrated safe profiles without cytotoxicity up to a concentration of 10 μM, and this cellular safety, combined with their anti-MERS-CoV antiviral activity, indicate all peptides can be regarded as potential promising antiviral agents.

Keywords: MERS-CoV; antivirals; coronavirus; drug discovery; fusion inhibitors.