Illustrating and homology modeling the proteins of the Zika virus

Abstract

The Zika virus (ZIKV) is a flavivirus of the family Flaviviridae, which is similar to dengue virus, yellow fever and West Nile virus. Recent outbreaks in South America, Latin America, the Caribbean and in particular Brazil have led to concern for the spread of the disease and potential to cause Guillain-Barré syndrome and microcephaly. Although ZIKV has been known of for over 60 years there is very little in the way of knowledge of the virus with few publications and no crystal structures. No antivirals have been tested against it either in vitro or in vivo. ZIKV therefore epitomizes a neglected disease. Several suggested steps have been proposed which could be taken to initiate ZIKV antiviral drug discovery using both high throughput screens as well as structure-based design based on homology models for the key proteins. We now describe preliminary homology models created for NS5, FtsJ, NS4B, NS4A, HELICc, DEXDc, peptidase S7, NS2B, NS2A, NS1, E stem, glycoprotein M, propeptide, capsid and glycoprotein E using SWISS-MODEL. Eleven out of 15 models pass our model quality criteria for their further use. While a ZIKV glycoprotein E homology model was initially described in the immature conformation as a trimer, we now describe the mature dimer conformer which allowed the construction of an illustration of the complete virion. By comparing illustrations of ZIKV based on this new homology model and the dengue virus crystal structure we propose potential differences that could be exploited for antiviral and vaccine design. The prediction of sites for glycosylation on this protein may also be useful in this regard. While we await a cryo-EM structure of ZIKV and eventual crystal structures of the individual proteins, these homology models provide the community with a starting point for structure-based design of drugs and vaccines as well as a for computational virtual screening.

The A–Z of Zika drug discovery

“…We also present a special section (see supplementary material online: viral entry and replication mechanisms). Initially, before the availability of ZIKV structures in early March 2016, there were several efforts to develop homology models of the ZIKV proteins based on close homologs such as dengue virus (DENV; see Glossary) and other flaviviruses [11][12][13]. Since late March 2016, ZIKV protein structures have been determined mostly by X-ray crystallography and have been made available in databases such as the Protein Data Bank (PDB) [14]: NS1, NS2B-NS3 protease, NS3 helicase, NS5 methyltransferase, NS5 polymerase, NS5 full-protein and envelope glycoprotein (Table 1).…”

Potential mechanisms of Zika‐linked microcephaly

“…Structural studies of ZIKV indicate that its protein coat, comprised primarily of envelope (E) protein, is similar to other flaviviruses . There may be ZIKV‐specific and/or strain‐specific changes associated with ten polymorphic amino acids around an asparagine‐linked carbohydrate moiety in the E protein, as this region appears to be subject to selective pressure upon multiple passages in insect cell lines …”

Déjà vu: Stimulating open drug discovery for SARS-CoV-2

“…We also described resources and molecules that could be prioritized for testing. This was followed by our homology modeling of every Zika virus protein [33] weeks before the first crystal structures for Zika proteins were released. All of this work was performed in the open and it attracted the attention of the IBM World Community Grid team who requested we submit a proposal to them for a Zika project using their distributed computing facilities.…”