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

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 , was identified by screening of a library of 6265 protease inhibitors. Molecular dynamics (MD) simulation studies revealed that compound formed a stable complex with ZIKV protease. Interaction analysis of compound 's binding pose from the cluster analysis of MD simulations trajectories predicted that mostly interacted with ZIKV NS3. Although designed as an aspartyl protease inhibitor, compound was found to inhibit ZIKV serine protease with IC = 143.25 ± 5.45 µM, in line with the results. Additionally, linear interaction energy method (LIE) was used to estimate binding affinities of compounds and (a known panflavivirus peptide hybrid with IC = 1.64 ± 0.015 µM against ZIKV protease). The LIE method correctly predicted the binding affinity of compound to be lower than that of , 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 represents a less polar and more drug-like non-peptide hit compound useful for further optimization.Communicated by Ramaswamy Sarma.