Potent, highly selective, and non-thiol inhibitors of protein geranylgeranyltransferase-I.
Potent, highly selective, and non-thiol inhibitors of protein geranylgeranyltransferase-I.
复制标题
蛋白质香叶基香叶基转移酶-I 的有效、高选择性、非硫醇抑制剂。
DOI：
10.1021/jm9900873
复制
发表时间：
1999
期刊：
影响因子：
--
通讯作者：
Hamilton,AD
中科院分区：
文献类型：
--
作者：
Vasudevan,A;Qian,Y;Vogt,A;Blaskovich,MA;Ohkanda,J;Sebti,SM;Hamilton,AD
设计、合成了一系列蛋白质香叶基香叶基转移酶-I（PGGT酶-I）的拟肽抑制剂，并进行了生物活性评价。这些抑制剂基于许多香叶基香叶基化蛋白质的C-末端CAAL序列。利用2-芳基-4-氨基苯甲酸衍生物作为中心二肽（AA）的模拟物，我们将一系列咪唑和吡啶衍生物连接到N-末端作为半胱氨酸替代物。这些不含巯基的肽模拟物对PGGT酶-I显示出优于密切相关的酶蛋白法尼基转移酶（PFTase）的特殊选择性。这种选择性保留在全细胞中，其中抑制剂显示阻断Rap-1A的香叶基香叶基化，而不影响小GTP结合蛋白如Ras的法尼基化。
The design, synthesis, and biological evaluation of a family of peptidomimetic inhibitors of protein geranylgeranyltransferase-I (PGGTase-I) are reported. The inhibitors are based on the C-terminal CAAL sequence of many geranylgeranylated proteins. Using 2-aryl-4-aminobenzoic acid derivatives as mimetics for the central dipeptide (AA), we have attached a series of imidazole and pyridine derivatives to the N-terminus as cysteine replacements. These non-thiol-containing peptidomimetics show exceptional selectivity for PGGTase-I over the closely related enzyme protein farnesyltransferase (PFTase). This selectivity is retained in whole cells where the inhibitors were shown to block the geranylgeranylation of Rap-1A without affecting the farnesylation of small GTP-binding proteins such as Ras.