Because of the small number of molecular targets in viruses and the rapid evolution of viral genes, it is very challenging to develop specific antiviral drugs. Viruses require host factors to translate their transcripts and targeting the host factor(s) offers a unique opportunity to develop antiviral drugs. It is well documented that some RNA viruses to enhance IRES-mediated viral genomic translation utilize an Internal Ribosome Entry Site (IRES). To accomplish this, viruses utilize a host’s protein, Receptor for Activated C Kinase 1 (RACK1), which is found to play a role in IRES-mediated viral translation. It is reported that RACK1 is an essential for hepatitis C virus (HCV), HIV1, CrPV and HSV1 translation and more than 80 different viruses are known to use IRES based translation. Therefore host RACK1 protein can be an attractive target for developing broad anti-viral drug. Depletion of host’s RACK1 will potentially inhibit virus replication. This background study has led us to the investigation for a possible development of novel antiviral therapeutics such RACK1 inhibitors or activators. By utilizing our lab developed crystal structure of the RACK1A protein from model plant <i>Arabidopsis</i>, and using a structure based drug design method, we discovered dozens of small compounds that can potentially inhibit the RACK1 functional tyrosine residue (Y248) phosphorylation. SD-29 is identified as the most potent binder to the RACK1A Y248 phosphorylation pocket. We found in-vitro studies that SD-29 can potentially repress viral (HCV and HIV1) IRES based luciferase reporter gene translation in HSB-1 and Hela cells. Current investigation is focused on the use of the compounds to inhibit virus proliferation.

Structure based discovery of host-targeted antiviral (HTA) small molecules: Ribosomal protein RACK1 as a potential broad antiviral target

254th National Meeting (2017)

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