Title:
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The myxobacterial metabolite ratjadone A inhibits HIV infection by blocking the Rev/CRM1-mediated nuclear export pathway
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Author:
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Fleta Soriano, Eric, 1983-; Martinez, Javier P.; Hinkelmann, Bettina; Gerth, Klaus; Washausen, Peter; Díez Antón, Juana, 1962-; Frank, Ronald; Sasse, Florenz; Meyerhans, Andreas
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Abstract:
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Background: The nuclear export of unspliced and partially spliced HIV-1 mRNA is mediated by the recognition of a leucine-rich nuclear export signal (NES) in the HIV Rev protein by the host protein CRM1/Exportin1. This makes the CRM1-Rev complex an attractive target for the development of new antiviral drugs. Here we tested the anti-HIV efficacy of ratjadone A, a CRM1 inhibitor derived from myxobacteria. Results: Ratjadone A inhibits HIV infection in vitro in a dose-dependent manner with EC50 values at the nanomolar range. The inhibitory effect of ratjadone A occurs around 12 hours post-infection and is specific for the Rev/CRM1-mediated nuclear export pathway. By using a drug affinity responsive target stability (DARTS) assay we could demonstrate that ratjadone A interferes with the formation of the CRM1-Rev-NES complex by binding to CRM1 but not to Rev. Conclusion: Ratjadone A exhibits strong anti-HIV activity but low selectivity due to toxic effects. Although this limits its potential use as a therapeutic drug, further studies with derivatives of ratjadones might help to overcome these difficulties in the future. |
Abstract:
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The research is supported by grants from the Bill and Melinda Gates Foundation, Institució Catalana de Recerca i Estudis Avancats (ICREA), the Spanish Ministry of Science and Innovation SAF2010-21336, BFU2010-20803 and FPI grant number BES-2011-048569 |
Subject(s):
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-RNA missatger -VIH (Virus) -Immunodeficiència -Ratjadone -Myxobacteria -HIV -Rev -Host factor -CRM1 -Nuclear export |
Rights:
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© 2014 Fleta-Soriano et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
http://creativecommons.org/licenses/by/2.0 |
Document type:
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Article Article - Published version |
Published by:
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BioMed Central
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