The myxobacterial metabolite ratjadone A inhibits HIV infection by blocking the Rev/CRM1-mediated nuclear export pathway

2.50
Hdl Handle:
http://hdl.handle.net/10033/620684
Title:
The myxobacterial metabolite ratjadone A inhibits HIV infection by blocking the Rev/CRM1-mediated nuclear export pathway
Authors:
Fleta-Soriano, Eric; Martinez, Javier P; Hinkelmann, Bettina; Gerth, Klaus; Washausen, Peter; Diez, Juana; Frank, Ronald; Sasse, Florenz; Meyerhans, Andreas
Abstract:
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.
Citation:
Microbial Cell Factories. 2014 Jan 29;13(1):17
Issue Date:
29-Jan-2014
URI:
http://dx.doi.org/10.1186/1475-2859-13-17; http://hdl.handle.net/10033/620684
Type:
Journal Article
Appears in Collections:
Publications of the research group Chemical Biology (CBIO)

Full metadata record

DC FieldValue Language
dc.contributor.authorFleta-Soriano, Ericen
dc.contributor.authorMartinez, Javier Pen
dc.contributor.authorHinkelmann, Bettinaen
dc.contributor.authorGerth, Klausen
dc.contributor.authorWashausen, Peteren
dc.contributor.authorDiez, Juanaen
dc.contributor.authorFrank, Ronalden
dc.contributor.authorSasse, Florenzen
dc.contributor.authorMeyerhans, Andreasen
dc.date.accessioned2017-01-06T10:25:34Z-
dc.date.available2017-01-06T10:25:34Z-
dc.date.issued2014-01-29en
dc.identifier.citationMicrobial Cell Factories. 2014 Jan 29;13(1):17en
dc.identifier.urihttp://dx.doi.org/10.1186/1475-2859-13-17en
dc.identifier.urihttp://hdl.handle.net/10033/620684-
dc.description.abstractAbstract 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.titleThe myxobacterial metabolite ratjadone A inhibits HIV infection by blocking the Rev/CRM1-mediated nuclear export pathwayen
dc.typeJournal Articleen
dc.language.rfc3066enen
dc.rights.holderFleta-Soriano et al.; licensee BioMed Central Ltd.en
dc.date.updated2015-09-04T08:31:31Zen
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