Synthesis and conformational analysis of peptide inhibitors of farnesyltransferase.

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.