Abstract
Zika virus (ZIKV) of the flaviviridae family, is the cause of emerging infections characterized by fever, Guillain-Barré syndrome (GBS) in adults and microcephaly in newborns. There exists an urgent unmet clinical need for anti-ZIKV drugs for the treatment of infected individuals. In the current work, we aimed at the promising virus drug target, ZIKV NS3 protease and constructed a Pharmacophore Anchor (PA) model for the active site. The PA model reveals a total of 12 anchors (E, H, V) mapped across the active site subpockets. We further identified five of these anchors to be critical core anchors (CEH1, CH3, CH7, CV1, CV3) conserved across flaviviral proteases. The ZIKV protease PA model was then applied in anchor-enhanced virtual screening yielding 14 potential antiviral candidates, which were tested by in vitro assays. We discovered FDA drugs Asunaprevir and Simeprevir to have potent anti-ZIKV activities with EC50 values 4.7 µM and 0.4 µM, inhibiting the viral protease with IC50 values 6.0 µM and 2.6 µM respectively. Additionally, the PA model anchors aided in the exploration of inhibitor binding mechanisms. In conclusion, our PA model serves as a promising guide map for ZIKV protease targeted drug discovery and the identified ‘previr’ FDA drugs are promising for anti-ZIKV treatments.
Highlights
The spread of Zika virus (ZIKV) from Asia and Africa to the Americas in recent years has raised alarms internationally
Sequence analysis involved multiple sequence alignment (MSA) of the ZIKV NS3 protease and NS2B cofactor domains (African strain MR766) with corresponding sequences from other mosquito-borne flaviviruses like Dengue virus (DENV), West Nile virus (WNV), Japanese encephalitis virus (JEV) and Murray Valley encephalitis virus (MVEV) followed by building phylogenetic trees summarized in Supplementary Fig. S1A
A significant global alignment of ZIKV NS2B cofactor and NS3 protease chains with the homologous counterparts is seen, most of the aligned residuesbeing highly conserved with many conserved sequence motifs with other viral proteases, it still contains some unique residue patterns
Summary
The spread of Zika virus (ZIKV) from Asia and Africa to the Americas in recent years has raised alarms internationally. The current work employs a structure-based pharmacophore anchor approach that incorporates comprehensive interaction patterns of the target binding site, giving a robust hotspot model beneficial to explore target functional mechanisms and applicable in inhibitor discovery and optimization. This strategy proved to be fruitful in understanding protein-compound binding mechanisms previously[24,25,26,27] and is applied to the ZIKV NS3 protease for studying consensus active site interactions and for inhibitor discovery via drug repurposing using FDA drugs. The PA model was employed for in silico ‘anchor-enhanced virtual screening’, a step-wise approach for screen inhibitors using anchors, progressing from our previous work on DENV protease where an anchor-based scoring function was used[27]
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