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

Fleta Soriano, Eric, 1983-; Martinez, Javier P.; Hinkelmann, Bettina; Gerth, Klaus; Washausen, Peter; Díez Antón, Juana, 1962-; Frank, Ronald; Sasse, Florenz; Meyerhans, Andreas

doi:http://dx.doi.org/10.1186/1475-2859-13-17

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

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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 10.1186/1475-2859-13-17

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.