Synthesis and conformational analysis of peptide inhibitors of farnesyltransferase

被引:12
作者
Byk, G
Lelievre, Y
Duchesne, M
Clerc, FF
Scherman, D
Guitton, JD
机构
[1] RHONE POULENC RORER,CNRS,UMR 133,F-94403 VITRY SUR SEINE,FRANCE
[2] RHONE POULENC RORER,DEPT BIOTECHNOL 13,F-94403 VITRY SUR SEINE,FRANCE
关键词
D O I
10.1016/S0968-0896(96)00210-6
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 but comparative conformational analysis studies by molecular dynamics of some of the here presented peptides and of our recently described peptidomimetic inhibitors of FTase. Copyright (C) 1997 Elsevier Science Ltd.
引用
收藏
页码:115 / 124
页数:10
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