Researchers have uncovered 110 potentially druggable antiviral targets and several existing drugs that may hit them by combining gene-trap insertional mutagenesis and a computational framework for repositioning molecules.
The approach, details of which were published in PLOS Computational Biology, is underpinned by the idea that knowledge of the molecular interactions between viruses and their hosts can lead to the discovery of druggable targets. Recognizing this, Feixiong Cheng, who now works at the Dana-Farber Cancer Institute, GeneTag Technology’s James Murray and researchers from Vanderbilt University School of Medicine set out to investigate which host genes are needed for viral replication.
Cheng and his collaborators applied gene-trap insertional mutagenesis to the problem. This entails disrupting host genes at random and watching what happens. If the disruption of a gene prevents a virus from replicating without killing the host cell, it could be a viable antiviral target.
By applying this approach to 10 cytotoxic mammalian viruses, one gram-negative bacterium and 5 toxins, the researchers uncovered 712 host genes of interest as drug targets. As a rule, the genes are ancient and have low evolutionary rates.
Most of the genes are unsuitable as drug targets, but, by incorporating known drug-gene signatures and bioinformatics data into the analysis, the researchers uncovered 110 that are worthy of further investigation. And by leveraging the Connectivity Map created by researchers at the Broad Institute, the team was able to identify drug that may hit the targets. Notable findings include evidence ajmaline, piroxicam and azlocillin may act against Ebola.