Insights into bioinformatic approaches for repurposing compounds as anti-viral drugs

Abstract

Background Drug repurposing is a cost-effective strategy to identify drugs with novel effects. We searched for drugs exhibiting inhibitory activity to Herpes Simplex virus 1 (HSV-1). Our strategy utilized gene expression data generated from HSV-1-infected cell cultures which was paired with drug effects on gene expression. Gene expression data from HSV-1 infected and uninfected neurons were analyzed using BaseSpace Correlation Engine (Illumina®). Based on the general Signature Reversing Principle (SRP), we hypothesized that the effects of candidate antiviral drugs on gene expression would be diametrically opposite (negatively correlated) to those effects induced by HSV-1 infection. Results We initially identified compounds capable of inducing changes in gene expression opposite to those which were consequent to HSV-1 infection. The most promising negatively correlated drugs (Valproic acid, Vorinostat) did not significantly inhibit HSV-1 infection further in African green monkey kidney epithelial cells (Vero cells). Next, we tested Sulforaphane and Menadione which showed effects similar to those caused by viral infections (positively correlated). Intriguingly, Sulforaphane caused a modest but significant inhibition of HSV-1 infection in Vero cells (IC50 = 180.4 µM, p = 0.008), but exhibited toxicity when further explored in human neuronal progenitor cells (NPCs) derived from induced pluripotent stem cells. Conclusions These results reveal the limits of the commonly used SRP strategy when applied to the identification of novel antiviral drugs and highlight the necessity to refine the SRP strategy to increase its utility.

The Impaired Neurodevelopment of Human Neural Rosettes in HSV-1-Infected Early Brain Organoids

“…The following HSV-1 strains were employed in this study: KOS (VR-1493; ATCC), and a previously detailed [ 14 , 15 ] KOS-based recombinant virus in which enhanced green fluorescent protein (EGFP) and monomeric red fluorescent protein (RFP) are reporters whose expression is driven by the viral promoters ICP0 and Glycoprotein C, respectively (HSV-1 DualFP).…”

“…Monolayer cultures of NPCs were derived from hiPSC line SC0000020 (subclone SF) as previously described [ 14 , 15 ]. NPCs were infected as monolayer cultures at a range of low multiplicities of infection (MOI 0.1–0.0001) with HSV-1, strain KOS, in the presence or absence of ACV.…”