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

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.

• Authors: Eric Fleta-Soriano, Javier P Martinez, Bettina Hinkelmann, Klaus Gerth, Peter Washausen, Juana Diez, Ronald Frank, Florenz Sasse, Andreas Meyerhans
• Journal: Microbial cell factories (Microb Cell Fact) Vol. 13 Pg. 17 (Jan 29 2014) ISSN: 1475-2859 [Electronic] England
• PMID: 24475978 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• HIV Core Protein p24
• Karyopherins
• Pyrones
• RNA, Messenger
• Receptors, Cytoplasmic and Nuclear
• exportin 1 protein
• p24 protein, Human Immunodeficiency Virus Type 1
• ratjadone
• rev Gene Products, Human Immunodeficiency Virus
• rev protein, Human Immunodeficiency Virus-1

Topics

• Active Transport, Cell Nucleus (drug effects)
• Antiviral Agents (pharmacology)
• Cell Line
• HIV Core Protein p24 (metabolism)
• HIV Infections (prevention & control)
• HIV-1 (metabolism)
• Humans
• Karyopherins (antagonists & inhibitors, metabolism)
• Myxococcales (metabolism)
• Protein Binding
• Pyrones (chemistry, metabolism, pharmacology)
• RNA, Messenger (metabolism)
• Receptors, Cytoplasmic and Nuclear (antagonists & inhibitors, metabolism)
• rev Gene Products, Human Immunodeficiency Virus (antagonists & inhibitors, metabolism)