Identification of Potential Broad‐Spectrum Peptidomimetic Antivirals Active Against Zika Virus

Abstract

Zika virus (ZIKV) has recently been the cause of major epidemics in South American countries especially Brazil. ZIKV has been identified as the cause of microcephaly in the fetuses of pregnant women and the Guillain‐Barre Syndrome, and to date, no therapeutics or vaccines are available against ZIKV infection. Previously, we reported the anti‐ZIKV activity of Heat Shock Protein (HSP) 70‐Interacting Peptide (HIP), a cell‐permeable hairpin peptide derived from the domain I of nonstructural protein 5A of hepatitis C virus (HCV). These results implicate the HSP70 family members in the pathogenesis of ZIKV, identify the HSP70 family proteins as potential host therapeutic targets against ZIKV, and present the HIP as a potential therapeutic agent with significant anti‐ZIKV activity. In this study, we performed rigorous in silico analyses to identify potential peptidomimetic compounds that mimic the binding of the HIP to HSP70. Through particle swarm optimization via SwarmDock, binding solutions were generated from crystal structures of HSP70 nucleotide binding domain (NBD) and NS5A Domain I. The highest‐ranked residue interactions were mapped through visualization software, which identified a common binding region at a pocket at the C‐terminus. Subsequent modeling at this pocket was used to generate a HIP‐binding model, independently confirmed through docking of HIP to HSP70‐NBD in AutoDock Vina. Virtual high‐throughput screening of a diverse compound library against the binding pocket identified putative leads. We are currently assessing the antiviral activity of the lead compounds in our cell culture model of ZIKV infection. Subsequently, the best leads will be optimized to achieve greater antiviral activity. As HIP also blocks HCV, the targeting of HSP70 may represent a broad‐spectrum approach for future antivirals. Targeting ZIKV and other Flaviviruses through host proteins provides a therapeutic target that avoids selection of resistant viral particles.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.