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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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    Authors
    Fleta-Soriano, Eric
    Martinez, Javier P
    Hinkelmann, Bettina
    Gerth, Klaus
    Washausen, Peter
    Diez, Juana
    Frank, Ronald cc
    Sasse, Florenz
    Meyerhans, Andreas
    Issue Date
    2014-01-29
    
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    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
    URI
    http://dx.doi.org/10.1186/1475-2859-13-17
    http://hdl.handle.net/10033/620684
    Type
    Journal Article
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    Publications of the research group Chemical Biology (CBIO)

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