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

Microbial Cell Factories

Research

Bettina Hinkelmann¹  Florenz Sasse¹  Peter Washausen¹  Ronald Frank¹  Eric Fleta-Soriano²  Javier P Martinez²  Andreas Meyerhans³  Juana Diez⁴  Klaus Gerth⁵ 

[1]Department of Chemical Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany

[2]Department of Experimental and Health Sciences, Infection Biology Group, Universitat Pompeu Fabra, Dr. Aiguader 88, 08003, Barcelona, Spain

[3]Department of Experimental and Health Sciences, Infection Biology Group, Universitat Pompeu Fabra, Dr. Aiguader 88, 08003, Barcelona, Spain

[4]Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

[5]Department of Experimental and Health Sciences, Molecular Virology Group, Universitat Pompeu Fabra, Barcelona, Spain

[6]Department of Microbial Drugs, Helmholtz Centre for Infection Research, Braunschweig, Germany

关键词: Ratjadone;    Myxobacteria;    HIV;    Rev;    Host factor;    CRM1;    Nuclear export;   

DOI  :  10.1186/1475-2859-13-17

 received in 2013-12-03, accepted in 2014-01-24,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundThe 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.ResultsRatjadone 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.ConclusionRatjadone 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.

【 授权许可】

Unknown   
© Fleta-Soriano et al.; licensee BioMed Central Ltd. 2014. This article is published under license to 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.