KMID : 0606920200280040311
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Biomolecules & Therapeutics 2020 Volume.28 No. 4 p.311 ~ p.319
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Small Molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Fusion by Targeting Cavities on Heptad Repeat Trimers
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Kandeel Mahmoud
Yamamoto Mizuki Al-Taher Abdulla Watanabe Aya Oh-hashi Kentaro Park Byoung-Kwon Kwon Hyung-Joo Inoue Jun-ichiro Al-Nazawi Mohammed
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Abstract
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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 ¥ìM, 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 ¥ìM with no observed toxicity in Vero cells at 10 ¥ìM. 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.
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KEYWORD
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MERS-CoV, Antiviral agents, Virtual screening, Plaques inhibition
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