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-ca
• dc.contributor.author Martinez, Javier P.ca
• dc.contributor.author Hinkelmann, Bettinaca
• dc.contributor.author Gerth, Klausca
• dc.contributor.author Washausen, Peterca
• dc.contributor.author Díez Antón, Juana, 1962-ca
• dc.contributor.author Frank, Ronaldca
• dc.contributor.author Sasse, Florenzca
• dc.contributor.author Meyerhans, Andreasca
• dc.date.accessioned 2015-03-19T08:38:06Z
• dc.date.available 2015-03-19T08:38:06Z
• dc.date.issued 2014ca
• 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.en
• 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-2011-048569en
• dc.format.mimetype application/pdfca
• 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 10.1186/1475-2859-13-17ca
• dc.identifier.doi http://dx.doi.org/10.1186/1475-2859-13-17
• dc.identifier.issn 1475-2859ca
• dc.identifier.uri http://hdl.handle.net/10230/23228
• dc.language.iso engca
• dc.publisher BioMed Centralca
• dc.relation.ispartof Microbial Cell Factories. 2014; 13: 17
• 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 © 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.ca
• dc.rights.accessRights info:eu-repo/semantics/openAccessca
• dc.rights.uri http://creativecommons.org/licenses/by/2.0
• dc.subject.keyword Ratjadoneen
• dc.subject.keyword Myxobacteriaen
• dc.subject.keyword HIVen
• dc.subject.keyword Reven
• dc.subject.keyword Host factoren
• dc.subject.keyword CRM1en
• dc.subject.keyword Nuclear exporten
• dc.subject.other RNA missatgerca
• dc.subject.other VIH (Virus)ca
• dc.subject.other Immunodeficiènciaca
• dc.title The myxobacterial metabolite ratjadone A inhibits HIV infection by blocking the Rev/CRM1-mediated nuclear export pathwayen
• dc.type info:eu-repo/semantics/articleca
• dc.type.version info:eu-repo/semantics/publishedVersionca