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


CONCLUSIONS
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.
Eric
E
Fleta-Soriano
Javier P
JP
Martinez
Bettina
B
Hinkelmann
Klaus
K
Gerth
Peter
P
Washausen
Juana
J
Diez
Ronald
R
Frank
Florenz
F
Sasse
Infection Biology Group, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Dr, Aiguader 88 08003, Barcelona, Spain. andreas.meyerhans@upf.edu.
Andreas
A
Meyerhans
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000998:Antiviral Agents / Q000494:pharmacology; D002460:Cell Line; D016655:HIV Core Protein p24 / Q000378:metabolism; D015658:HIV Infections / Q000517:prevention & control*; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D028884:Karyopherins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009231:Myxococcales / Q000378:metabolism*; D011485:Protein Binding; D011753:Pyrones / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054321:rev Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000097606:Exportin 1 Protein
D000998:Antiviral Agents; D016655:HIV Core Protein p24; D028884:Karyopherins; D011753:Pyrones; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D054321:rev Gene Products, Human Immunodeficiency Virus; D000097606:Exportin 1 Protein; C514799:p24 protein, Human Immunodeficiency Virus Type 1; C429103:ratjadone; C514860:rev protein, Human Immunodeficiency Virus-1