Small Molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Fusion by Targeting Cavities on Heptad Repeat Trimers

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.

Differential Signaling and Virus Production in Calu-3 Cells and Vero Cells upon SARS-CoV-2 Infection

“…Vero cells (2×10 5 cells/well in 6-well plates) were cultured in DMEM containing 10% FBS at 37°C in a CO 2 incubator overnight ( Park et al ., 2019 ; Kandeel et al ., 2020 ). The cells were washed with phosphate-buffered saline (PBS), SARS-CoV-2 in PBS at MOI 0.01 was added into each well, and the plates were incubated for 1 h at 37°C in a CO 2 incubator.…”

Drug Development and Medicinal Chemistry Efforts toward SARS‐Coronavirus and Covid‐19 Therapeutics

“…The activity led to the identification of three promising derivatives. Among them, compound 131 (IC 50 =21.8 μM), at 10 μM concentration, was able to produce 74.5 % reduction in MERS‐CoV plaques formation, with low cell toxicity (HEK293 and Vero cells), and favorable predicted drug‐like parameters …”

A pilot study of the antiviral activity of anionic and cationic polyamidoamine dendrimers against the Middle East respiratory syndrome coronavirus

“…Three new small-molecule fusion inhibitors were developed by targeting the fusion core protein. 22 The natural phenolic derivative resveratrol showed potent anti-…”