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)
  • 투고 : 2019.12.02
  • 심사 : 2020.01.23
  • 발행 : 2020.07.01


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.



The authors acknowledge the Deanship of Scientific Research at King Faisal University for the financial support under Strategic projects track (Grant No. 171001). Hyung-Joo Kwon was supported by grants from the National Research Foundation (2016M3A9B6916708) funded by the Ministry of Science and ICT in the Republic of Korea. This work was supported in part by grants-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (16H06575 to JI), from the Japan Society for the Promotion of Science [18K15235 to MY, 16H06276 AdAMS) to J.I.], and by the Japan Agency for Medical Research and Development (AMED) [Program of Japan Initiative for Global Research Network on Infectious Diseases (JGRID) JP18fm0108006 to MY and JI].


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