Identification of a C2-symmetric diol based human immunodeficiency virus protease inhibitor targeting Zika virus NS2B-NS3 protease

Abstract

Zika virus (ZIKV) is an emerging mosquito-borne flavivirus and infection by ZIKV Asian lineage is known to cause fetal brain anomalies and Guillain-Barrés syndrome. The WHO declared ZIKV a global public health emergency in 2016. However, currently neither vaccines nor antiviral prophylaxis/treatments are available. In this study, we report the identification of a C2-symmetric diol-based Human immunodeficiency virus type-1 (HIV) protease inhibitor active against ZIKV NS2B-NS3 protease. The compound, referred to as <b>9b</b>, was identified by <i>in silico</i> screening of a library of 6265 protease inhibitors. Molecular dynamics (MD) simulation studies revealed that compound <b>9b</b> formed a stable complex with ZIKV protease. Interaction analysis of compound <b>9b</b>'s binding pose from the cluster analysis of MD simulations trajectories predicted that <b>9b</b> mostly interacted with ZIKV NS3. Although designed as an aspartyl protease inhibitor, compound <b>9b</b> was found to inhibit ZIKV serine protease <i>in vitro</i> with IC₅₀ = 143.25 ± 5.45 µM, in line with the <i>in silico</i> results. Additionally, linear interaction energy method (LIE) was used to estimate binding affinities of compounds <b>9b</b> and <b>86</b> (a known panflavivirus peptide hybrid with IC₅₀ = 1.64 ± 0.015 µM against ZIKV protease). The LIE method correctly predicted the binding affinity of compound <b>86</b> to be lower than that of <b>9b</b>, proving to be superior to the molecular docking methods in scoring and ranking compounds. Since most of the reported ZIKV protease inhibitors are positively charged peptide-hybrids, with our without electrophilic warheads, compound <b>9b</b> represents a less polar and more drug-like non-peptide hit compound useful for further optimization.Communicated by Ramaswamy Sarma.