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

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 ef...

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Autores principales: Zheng, Wenxiao, D’Aiuto, Leonardo, Demers, Matthew J, Muralidaran, Vaishali, Wood, Joel A, Wesesky, Maribeth, Chattopadhyay, Ansuman, Nimgaonkar, Vishwajit L
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8411619/
https://www.ncbi.nlm.nih.gov/pubmed/34463534
http://dx.doi.org/10.1177/20402066211036822
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author Zheng, Wenxiao
D’Aiuto, Leonardo
Demers, Matthew J
Muralidaran, Vaishali
Wood, Joel A
Wesesky, Maribeth
Chattopadhyay, Ansuman
Nimgaonkar, Vishwajit L
author_facet Zheng, Wenxiao
D’Aiuto, Leonardo
Demers, Matthew J
Muralidaran, Vaishali
Wood, Joel A
Wesesky, Maribeth
Chattopadhyay, Ansuman
Nimgaonkar, Vishwajit L
author_sort Zheng, Wenxiao
collection PubMed
description 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.
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spelling pubmed-84116192021-09-03 Insights into bioinformatic approaches for repurposing compounds as anti-viral drugs Zheng, Wenxiao D’Aiuto, Leonardo Demers, Matthew J Muralidaran, Vaishali Wood, Joel A Wesesky, Maribeth Chattopadhyay, Ansuman Nimgaonkar, Vishwajit L Antivir Chem Chemother Original Article 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. SAGE Publications 2021-08-31 /pmc/articles/PMC8411619/ /pubmed/34463534 http://dx.doi.org/10.1177/20402066211036822 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by-nc/4.0/Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
spellingShingle Original Article
Zheng, Wenxiao
D’Aiuto, Leonardo
Demers, Matthew J
Muralidaran, Vaishali
Wood, Joel A
Wesesky, Maribeth
Chattopadhyay, Ansuman
Nimgaonkar, Vishwajit L
Insights into bioinformatic approaches for repurposing compounds as anti-viral drugs
title Insights into bioinformatic approaches for repurposing compounds as anti-viral drugs
title_full Insights into bioinformatic approaches for repurposing compounds as anti-viral drugs
title_fullStr Insights into bioinformatic approaches for repurposing compounds as anti-viral drugs
title_full_unstemmed Insights into bioinformatic approaches for repurposing compounds as anti-viral drugs
title_short Insights into bioinformatic approaches for repurposing compounds as anti-viral drugs
title_sort insights into bioinformatic approaches for repurposing compounds as anti-viral drugs
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8411619/
https://www.ncbi.nlm.nih.gov/pubmed/34463534
http://dx.doi.org/10.1177/20402066211036822
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