Wolff B, Sanglier J J, Wang Y
Sandoz Research Institute, Brunner Strasse 59, A1230 Vienna, Austria.
Chem Biol. 1997 Feb;4(2):139-47. doi: 10.1016/s1074-5521(97)90257-x.
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.
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.
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.
1型人类免疫缺陷病毒（HIV-1）的调节蛋白Rev是未剪接和不完全剪接的病毒mRNA出现在细胞质中所必需的，因此也是病毒复制所必需的。如果Rev要发挥作用，它从细胞核到细胞质的转运是必不可少的。我们希望鉴定出这种转运过程的抑制剂，因为它们可能是潜在的抗病毒药物。
链霉菌代谢产物细霉素B以及细霉素/和佐久间霉素家族的其他抗生素被鉴定为Rev核质转运的抑制剂，其浓度为纳摩尔级。细霉素B也会阻断mRNA依赖Rev的向细胞质的输出，在短期转染实验中，它会抑制依赖Rev但不依赖Rev的基因表达。在原代人单核细胞中，细霉素B可抑制HIV-1复制。
细霉素B是首个被鉴定出的低分子量核输出抑制剂。尽管它不能用于治疗，但它应作为剖析核输出途径的有价值工具。
