Zika virus Therapeutics: Drug Targets and Repurposing Medicine from the Human Genome

Abstract

Zika viral infection is caused by an emerging mosquito-borne virus, the Zika virus (ZIKV) and threatens to become a global pandemic. While not life threatening, the Zika Virus Disease (ZVD) is suspected to be associated with severe neurological disorders including Guillain-Barré syndrome and microcephaly. Currently, no known cure or diagnostic tests for ZVD are available. The host cell molecular targets are unknown for ZIKV. The ZIKV is related to various other mosquito borne viruses including the Chikungunya, Dengue, Japanese encephalitis, Spondweni, Yellow fever and West Nile viruses. The host cell targets are known for most of these viruses. All of these viruses harbor common protein motifs and domains, raising the possibility of shared molecular targets in the host genome. To facilitate target(s) discovery for the ZIKV therapy, the disease-and protein-knowledge databases were datamined for Zika-related viruses. An initial database of 251 genes was established. Additional filtering using variants associated with the Zika-related viruses and neurological disease phenotypes, identified 55 putative candidate ZIKV targets. These encompass druggable proteins including adhesion molecules, chemokines, enzymes, interleukins, receptors and transporters. Genes linked to Guillain-Barré syndrome and microcephaly was among the Zika candidate genes. The protein expression of the candidate genes was detected in diverse body fluids. Drug bank datamining of these candidate targets identified seventy-nine FDA-approved drugs of the class antineoplastics, anti diabetic, anti-inflammatory, antivirals, antibiotics, statins and neutraceuticals. The database of genes from the study provides a framework for diagnosis and therapy of the ZVD. The FDA-approved list of drugs, if verified, may offer a repurposing use for the treatment of the ZVD.

Zika Virus Therapeutic Lead Compounds Discovery Using Chemoinformatics Approaches

“…However, recently efforts to identify host cell targets as well as to develop a rationale for repurposed drugs are beginning to shed light. Using bioinformatics approaches and the protein sequence homology across diverse flaviviruses, a database of candidate ZIKV-related genes and a pipeline of FDA approved drugs were developed [35]. In another study, Hamel et al showed that human dermal fibroblasts, epidermal keratinocytes and immature dendritic cells are permissive to the most recent ZIKV isolate, responsible for the epidemic in French Polynesia [36].…”

“…The bioinformatics and proteomics tools used in the study have been described in detail [33,35,38]. The protein annotation and chemoinformatics analysis of the ZIKV-related genes was performed using the canSAR 2.0 integrated knowledgebase, a publically available database [37].…”

“…Two recent reports have identified putative candidate genes in the host cell genome for the ZIKV. In one study using bioinformatics approaches, 55 host cell targets were identified for the Zika-related viruses [35]. Based on these targets, a pipeline of 79 FDA approved drugs was predicted for therapeutic use in the ZVD.…”

“…A recently described database of ZIKV related genes [35,36] were subjected to chemoinformatics analysis using the canSAR integrated protein annotation tool [37]. Using ligand-based druggability analysis scores, RO5 compliant active hit compounds (IC 50 < 100nM) for 35 ZIKV targets were identified.…”

Repurposing Drugs in the Genomics Era: Bioinformatics Approaches

“…28 The drug classes included antidiabetics, anti estrogens, antineoplastics, antithrombotics, antivirals, antihypertensives, statins as well as nutraceuticals. These results provide a strong rationale for therapeutic validation for repurposing efforts for these infectious diseases.…”