Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Small Molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Fusion by Targeting Cavities on Heptad Repeat Trimers

  • 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) ;
  • Al-Taher, Abdulla (Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University) ;
  • Watanabe, Aya (Division of Cellular and Molecular Biology, Department of Cancer Biology, Institute of Medical Science, The University of Tokyo) ;
  • Oh-hashi, Kentaro (Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University) ;
  • 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 (Research Center for Asian Infectious Diseases, Institute of Medical Science, The University of Tokyo) ;
  • Al-Nazawi, Mohammed (Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University)
  • Received : 2019.12.02
  • Accepted : 2020.01.23
  • Published : 2020.07.01
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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 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

References

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