Byk G, Lelievre Y, Duchesne M, Clerc F F, Scherman D, Guitton J D
Rhône-Poulenc Rorer, UMR-133 RPR-CNRS, Vitry Sur Seine, France.
Bioorg Med Chem. 1997 Jan;5(1):115-24. doi: 10.1016/s0968-0896(96)00210-6.
Farnesylation of the ras oncogene product by Farnesyl Transferase (FTase) is known to be a critical step in cell transformation leading to uncontrolled proliferation. The peptide CysValTicMet is a potent FTase inhibitor, but its degradation by amino-peptidases and its only weak internalization into cells make it a bad candidate for a future cancer drug. We have prepared improved CysValTicMet analogues using several approaches: (i) amino terminal modifications or introduction of pseudopeptides or non-natural amino acids to increase proteolytic stability, (ii) introduction of hydrophobic aliphatic chains to increase cell internalization and metabolic stability and (iii) transformation into prodrugs. Additionally, we have carried out comparative conformational analysis studies by molecular dynamics of some of the here presented peptides and of our recently described peptidomimetic inhibitors of FTase.
已知法尼基转移酶（FTase）对ras癌基因产物进行法尼基化是细胞转化导致不受控制的增殖过程中的关键步骤。肽CysValTicMet是一种有效的FTase抑制剂，但其会被氨肽酶降解，并且仅能微弱地内化进入细胞，这使其成为未来癌症药物的不佳候选物。我们采用了几种方法制备了改进的CysValTicMet类似物：（i）氨基末端修饰或引入假肽或非天然氨基酸以提高蛋白水解稳定性；（ii）引入疏水脂肪链以增加细胞内化和代谢稳定性；（iii）转化为前药。此外，我们通过分子动力学对本文中呈现的一些肽以及我们最近描述的FTase拟肽抑制剂进行了比较构象分析研究。
