Department of Dermatology, University of Rochester, Rochester, NY 14642, USA.
J Med Chem. 2010 Aug 26;53(16):6018-27. doi: 10.1021/jm100231t.
Production of the Gag-Pol polyprotein in human immunodeficiency virus (HIV) requires a -1 ribosomal frameshift, which is directed by a highly conserved RNA stem-loop. Building on our discovery of a set of disulfide-containing peptides that bind this RNA, we describe medicinal chemistry efforts designed to begin to understand the structure-activity relationships and RNA sequence-selectivity relationships associated with these compounds. Additionally, we have prepared analogues incorporating an olefin or saturated hydrocarbon bioisostere of the disulfide moiety, as a first step toward enhancing biostability. The olefin-containing compounds exhibit affinity comparable to the lead disulfide and, importantly, have no discernible toxicity when incubated with human fibroblasts at concentrations up to 1 mM.
在人类免疫缺陷病毒 (HIV) 中，Gag-Pol 多聚蛋白的产生需要一个 -1 核糖体移码，该移码由一个高度保守的 RNA 茎环引导。基于我们发现的一组结合这种 RNA 的含二硫键的肽，我们描述了旨在开始理解与这些化合物相关的结构-活性关系和 RNA 序列选择性关系的药物化学研究。此外，我们还制备了含有二硫键部分的烯烃或饱和烃生物等排体的类似物，作为提高生物稳定性的第一步。含烯烃的化合物表现出与先导二硫化物相当的亲和力，重要的是，在高达 1mM 的浓度下与人成纤维细胞孵育时没有明显的毒性。
