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Combating Ebola with Repurposed Therapeutics Using the CANDO Platform

Ebola virus disease (EVD) is extremely virulent with an estimated mortality rate of up to 90%. However, the state-of-the-art treatment for EVD is limited to quarantine and supportive care. The 2014 Ebola epidemic in West Africa, the largest in history, is believed to have caused more than 11,000 fat...

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Autores principales: Chopra, Gaurav, Kaushik, Sashank, Elkin, Peter L., Samudrala, Ram
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958544/
https://www.ncbi.nlm.nih.gov/pubmed/27898018
http://dx.doi.org/10.3390/molecules21121537
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author Chopra, Gaurav
Kaushik, Sashank
Elkin, Peter L.
Samudrala, Ram
author_facet Chopra, Gaurav
Kaushik, Sashank
Elkin, Peter L.
Samudrala, Ram
author_sort Chopra, Gaurav
collection PubMed
description Ebola virus disease (EVD) is extremely virulent with an estimated mortality rate of up to 90%. However, the state-of-the-art treatment for EVD is limited to quarantine and supportive care. The 2014 Ebola epidemic in West Africa, the largest in history, is believed to have caused more than 11,000 fatalities. The countries worst affected are also among the poorest in the world. Given the complexities, time, and resources required for a novel drug development, finding efficient drug discovery pathways is going to be crucial in the fight against future outbreaks. We have developed a Computational Analysis of Novel Drug Opportunities (CANDO) platform based on the hypothesis that drugs function by interacting with multiple protein targets to create a molecular interaction signature that can be exploited for rapid therapeutic repurposing and discovery. We used the CANDO platform to identify and rank FDA-approved drug candidates that bind and inhibit all proteins encoded by the genomes of five different Ebola virus strains. Top ranking drug candidates for EVD treatment generated by CANDO were compared to in vitro screening studies against Ebola virus-like particles (VLPs) by Kouznetsova et al. and genetically engineered Ebola virus and cell viability studies by Johansen et al. to identify drug overlaps between the in virtuale and in vitro studies as putative treatments for future EVD outbreaks. Our results indicate that integrating computational docking predictions on a proteomic scale with results from in vitro screening studies may be used to select and prioritize compounds for further in vivo and clinical testing. This approach will significantly reduce the lead time, risk, cost, and resources required to determine efficacious therapies against future EVD outbreaks.
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spelling pubmed-59585442018-05-18 Combating Ebola with Repurposed Therapeutics Using the CANDO Platform Chopra, Gaurav Kaushik, Sashank Elkin, Peter L. Samudrala, Ram Molecules Article Ebola virus disease (EVD) is extremely virulent with an estimated mortality rate of up to 90%. However, the state-of-the-art treatment for EVD is limited to quarantine and supportive care. The 2014 Ebola epidemic in West Africa, the largest in history, is believed to have caused more than 11,000 fatalities. The countries worst affected are also among the poorest in the world. Given the complexities, time, and resources required for a novel drug development, finding efficient drug discovery pathways is going to be crucial in the fight against future outbreaks. We have developed a Computational Analysis of Novel Drug Opportunities (CANDO) platform based on the hypothesis that drugs function by interacting with multiple protein targets to create a molecular interaction signature that can be exploited for rapid therapeutic repurposing and discovery. We used the CANDO platform to identify and rank FDA-approved drug candidates that bind and inhibit all proteins encoded by the genomes of five different Ebola virus strains. Top ranking drug candidates for EVD treatment generated by CANDO were compared to in vitro screening studies against Ebola virus-like particles (VLPs) by Kouznetsova et al. and genetically engineered Ebola virus and cell viability studies by Johansen et al. to identify drug overlaps between the in virtuale and in vitro studies as putative treatments for future EVD outbreaks. Our results indicate that integrating computational docking predictions on a proteomic scale with results from in vitro screening studies may be used to select and prioritize compounds for further in vivo and clinical testing. This approach will significantly reduce the lead time, risk, cost, and resources required to determine efficacious therapies against future EVD outbreaks. MDPI 2016-11-25 /pmc/articles/PMC5958544/ /pubmed/27898018 http://dx.doi.org/10.3390/molecules21121537 Text en © 2016 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Chopra, Gaurav
Kaushik, Sashank
Elkin, Peter L.
Samudrala, Ram
Combating Ebola with Repurposed Therapeutics Using the CANDO Platform
title Combating Ebola with Repurposed Therapeutics Using the CANDO Platform
title_full Combating Ebola with Repurposed Therapeutics Using the CANDO Platform
title_fullStr Combating Ebola with Repurposed Therapeutics Using the CANDO Platform
title_full_unstemmed Combating Ebola with Repurposed Therapeutics Using the CANDO Platform
title_short Combating Ebola with Repurposed Therapeutics Using the CANDO Platform
title_sort combating ebola with repurposed therapeutics using the cando platform
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958544/
https://www.ncbi.nlm.nih.gov/pubmed/27898018
http://dx.doi.org/10.3390/molecules21121537
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