Predicting Zika virus structural biology: Challenges and opportunities for intervention

Abstract

Background: Zika virus is an emerging crisis as infection is implicated in severe neurological disorders—Guillain–Barré syndrome and fetal microcephaly. There are currently no treatment options available for Zika virus infection. This virus is part of the flavivirus genus and closely related to Dengue Fever Virus, West Nile Virus, and Japanese Encephalitis Virus. Like other flaviviruses, the Zika virus genome encodes three structural proteins (capsid, precursor membrane, and envelope) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). Currently, no structural information exists on these viral proteins to facilitate vaccine design and rational drug discovery. Methods: Structures for all Zika virus viral proteins were predicted using experimental templates available from closely related viruses using the online SwissModel server. These homology models were compared to drug targets from other viruses using Visual Molecular Dynamics Multiseq software. Sequential alignment of all Zika virus polyproteins was performed using Clustal Omega to identify mutations in specific viral proteins implicated in pathogenesis. Results: The precursor membrane, envelope, and NS1 proteins are unique to Zika virus highlighting possible challenges in vaccine design. Sequential differences between Zika virus strains occur at critical positions on precursor membrane, envelope, NS2A, NS3, NS4B, and NS5 as potential loci for differential pathogenesis. Druggable pockets in Dengue Fever Virus and West Nile Virus NS3 and NS5 are retained in predicted Zika virus structures. Conclusions: Lead candidates for Zika virus can likely be established using NS3 and NS5 inhibitors from other flaviviruses, and the structures presented can provide opportunities for Zika virus intervention strategies.