Leptomycin B is an inhibitor of nuclear export: inhibition of nucleo-cytoplasmic translocation of the human immunodeficiency virus type 1 (HIV-1) Rev protein and Rev-dependent mRNA.
BACKGROUND
The human immunodeficiency virus type 1 (HIV-1) regulatory protein Rev is required for unspliced and incompletely spliced viral mRNAs to appear in the cytoplasm and thus for viral replication. Translocation of Rev from the nucleus to the cytoplasm is essential if Rev is to function. We wanted to identify inhibitors of this transport process because they would be potential antiviral agents.


RESULTS
The Streptomyces metabolite, leptomycin B, and other antibiotics of the leptomycin/kazusamycin family were identified as inhibitors of the nucleo-cytoplasmic translocation of Rev at nanomolar concentrations. Rev-dependent export of mRNA into the cytoplasm is also blocked by leptomycin B, which inhibits Rev-dependent, but not Rev-independent gene expression in a short-term transfection assay. In primary human monocytes, leptomycin B suppresses HIV-1 replication.


CONCLUSIONS
Leptomycin B is the first low molecular weight inhibitor of nuclear export to be identified. Although it cannot be used therapeutically, it should serve as a valuable tool for dissecting nuclear export pathways.
Wolff
B
B
Sandoz Research Institute, Brunner Strasse 59, A1230 Vienna, Austria. wolff_b@a1.wienv1.sandoz.com
Sanglier
J J
JJ
Wang
Y
Y
D017398:Alternative Splicing; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001692:Biological Transport; D019556:COS Cells; D003593:Cytoplasm / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D015967:Gene Expression Regulation, Viral; D015694:Gene Products, rev / Q000378:metabolism*; D015497:HIV-1; D006801:Humans; D009000:Monocytes / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D054321:rev Gene Products, Human Immunodeficiency Virus
D000903:Antibiotics, Antineoplastic; D005231:Fatty Acids, Unsaturated; D015694:Gene Products, rev; D012333:RNA, Messenger; D054321:rev Gene Products, Human Immunodeficiency Virus; C038753:leptomycin B