BENZODIAZEPINE PEPTIDOMIMETICS - POTENT INHIBITORS OF RAS FARNESYLATION IN ANIMAL-CELLS
BENZODIAZEPINE PEPTIDOMIMETICS - POTENT INHIBITORS OF RAS FARNESYLATION IN ANIMAL-CELLS
复制标题
DOI：
10.1126/science.8316834
复制
发表时间：
1993-06-25
期刊：
影响因子：
56.9
通讯作者：
MARSTERS, JC
中科院分区：
文献类型：
--
作者：
JAMES, GL;GOLDSTEIN, JL;MARSTERS, JC
致癌Ras蛋白仅在其羧基末端附近的半胱氨酸上附着法尼基残基修饰时才能将动物细胞转化为恶性表型。催化该反应的法尼基转移酶识别CAAX序列的四肽，其中C是半胱氨酸，A是脂肪氨基酸，X是羧基末端蛋氨酸或丝氨酸。用基于苯二氮卓类的肽转化模拟物取代两个脂肪族残基，产生了有效的法尼基转移酶抑制剂[50%抑制浓度(IC50) < 1 nM]。与四肽不同，苯二氮卓类拟肽物进入细胞并阻断法尼基与Ras、核层蛋白和其他几种蛋白质的附着。在微摩尔浓度下，这些抑制剂恢复了ras转化细胞的正常生长模式。苯二氮卓类肽类药物可用于设计肿瘤的治疗方案，其中致癌的Ras蛋白可导致肿瘤的异常生长，如结肠、肺和胰腺。
Oncogenic Ras proteins transform animal cells to a malignant phenotype only when modified by farnesyl residues attached to cysteines near their carboxyl termini. The farnesyltransferase that catalyzes this reaction recognizes tetrapeptides of the sequence CAAX, where C is cysteine, A is an aliphatic amino acid, and X is a carboxyl-terminal methionine or serine. Replacement of the two aliphatic residues with a benzodiazepine-based mimic of a peptide turn generated potent inhibitors of farnesyltransferase [50 percent inhibitory concentration (IC50) < 1 nM]. Unlike tetrapeptides, the benzodiazepine peptidomimetics enter cells and block attachment of farnesyl to Ras, nuclear lamins, and several other proteins. At micromolar concentrations, these inhibitors restored a normal growth pattern to Ras-transformed cells. The benzodiazepine peptidomimetics may be useful in the design of treatments for tumors in which oncogenic Ras proteins contribute to abnormal growth, such as that of the colon, lung, and pancreas.