Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2019.202
Small Molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Fusion by Targeting Cavities on Heptad Repeat Trimers
Mahmoud Kandeel1,2,*, Mizuki Yamamoto3,4, Abdulla Al-Taher1, Aya Watanabe4, Kentaro Oh-hashi5, Byoung Kwon Park6, Hyung-Joo Kwon6,*, Jun-ichiro Inoue3,4 and Mohammed Al-Nazawi1
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,
4Division of Cellular and Molecular Biology, Department of Cancer Biology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639,
5Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Gifu 501-1193, Japan
6Department of Microbiology, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea
*E-mail: mkandeel@kfu.edu.sa (Kandeel M), hjookwon@hallym.ac.kr (Kwon HJ)
Tel: +966-568918734 (Kandeel M), +82-33-248-2635 (Kwon HJ)
Fax: +966-13-589-6617 (Kandeel M), +82-33-241-3640 (Kwon HJ)
Received: December 2, 2019; Revised: January 13, 2020; Accepted: January 23, 2020; Published online: March 4, 2020.
© The Korean Society of Applied Pharmacology. All rights reserved.

Abstract
Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a newly emerging viral disease with fatal outcomes. However, no MERS-CoV-specific treatment is commercially available. Given the absence of previous structure-based drug discovery studies targeting MERS-CoV fusion proteins, this set of compounds is considered the first generation of MERS-CoV small molecule fusion inhibitors. After a virtual screening campaign of 1.56 million compounds followed by cell-cell fusion assay and MERS-CoV plaques inhibition assay, three new compounds were identified. Compound numbers 22, 73, and 74 showed IC50 values of 12.6, 21.8, and 11.12 µM, respectively, and were most effective at the onset of spike-receptor interactions. The compounds exhibited safe profiles against Human embryonic kidney cells 293 (HEK293) at a concentration of 20 µM with no observed toxicity in Vero cells at 10 µM. The experimental results are accompanied with predicted favorable pharmacokinetic descriptors and drug-likeness parameters. In conclusion, this study provides the first generation of MERS-CoV fusion inhibitors with potencies in the low micromolar range.
Keywords: MERS-CoV, Antiviral agents, Virtual screening, Plaques inhibition

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