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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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dc.contributor.author Fleta Soriano, Eric, 1983-
dc.contributor.author Martinez, Javier P.
dc.contributor.author Hinkelmann, Bettina
dc.contributor.author Gerth, Klaus
dc.contributor.author Washausen, Peter
dc.contributor.author Díez Antón, Juana, 1962-
dc.contributor.author Frank, Ronald
dc.contributor.author Sasse, Florenz
dc.contributor.author Meyerhans, Andreas
dc.date.accessioned 2015-03-19T08:38:06Z
dc.date.available 2015-03-19T08:38:06Z
dc.date.issued 2014
dc.identifier.citation Fleta-Soriano E, Martinez JP, Hinkelmann B, Gerth K, Washausen P, Diez J, Frank R, Sasse F, Meyerhans A. The myxobacterial metabolite ratjadone A inhibits HIV infection by blocking the Rev/CRM1-mediated nuclear export pathway. Microbial Cell Factories. 2014; 13: 17. DOI 10.1186/1475-2859-13-17
dc.identifier.issn 1475-2859
dc.identifier.uri http://hdl.handle.net/10230/23228
dc.description.abstract 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.
dc.description.sponsorship 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
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher BioMed Central
dc.relation.ispartof Microbial Cell Factories. 2014; 13: 17
dc.rights © 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.
dc.rights.uri http://creativecommons.org/licenses/by/2.0
dc.subject.other RNA missatger
dc.subject.other VIH (Virus)
dc.subject.other Immunodeficiència
dc.title The myxobacterial metabolite ratjadone A inhibits HIV infection by blocking the Rev/CRM1-mediated nuclear export pathway
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1186/1475-2859-13-17
dc.subject.keyword Ratjadone
dc.subject.keyword Myxobacteria
dc.subject.keyword HIV
dc.subject.keyword Rev
dc.subject.keyword Host factor
dc.subject.keyword CRM1
dc.subject.keyword Nuclear export
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2010-21336
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/BFU2010-20803
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/BES2011-048569
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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