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    Identification of myxobacteria-derived HIV inhibitors by a high-throughput two-step infectivity assay

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    Authors
    Martinez, Javier P
    Hinkelmann, Bettina
    Fleta-Soriano, Eric
    Steinmetz, Heinrich
    Jansen, Rolf
    Diez, Juana
    Frank, Ronald cc
    Sasse, Florenz
    Meyerhans, Andreas
    Issue Date
    2013-09-24
    
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    Abstract
    Abstract Background Drug-resistance and therapy failure due to drug-drug interactions are the main challenges in current treatment against Human Immunodeficiency Virus (HIV) infection. As such, there is a continuous need for the development of new and more potent anti-HIV drugs. Here we established a high-throughput screen based on the highly permissive TZM-bl cell line to identify novel HIV inhibitors. The assay allows discriminating compounds acting on early and/or late steps of the HIV replication cycle. Results The platform was used to screen a unique library of secondary metabolites derived from myxobacteria. Several hits with good anti-HIV profiles were identified. Five of the initial hits were tested for their antiviral potency. Four myxobacterial compounds, sulfangolid C, soraphen F, epothilon D and spirangien B, showed EC50 values in the nM range with SI > 15. Interestingly, we found a high amount of overlapping hits compared with a previous screen for Hepatitis C Virus (HCV) using the same library. Conclusion The unique structures and mode-of-actions of these natural compounds make myxobacteria an attractive source of chemicals for the development of broad-spectrum antivirals. Further biological and structural studies of our initial hits might help recognize smaller drug-like derivatives that in turn could be synthesized and further optimized.
    Citation
    Microbial Cell Factories. 2013 Sep 24;12(1):85
    URI
    http://dx.doi.org/10.1186/1475-2859-12-85
    http://hdl.handle.net/10033/620702
    Type
    Journal Article
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    Publications of the research group Chemical Biology (CBIO)

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