Yves Lelièvre

Constrained analogs of KCVFM with improved inhibitory properties against farnesyl transferase

Abstract Constrained analogs of KCVFM, reported thus far as one of the most active peptidic inhibitors of farnesyl transferase, have been synthesized. Replacement of Val-Phe with Val-Tic and (N-Me)Val-Tic led to dramatically more active analogs possessing favored extended conformations. Based on molecular modelling studies the design and synthesis of various conformational probes to be substituted for Val and Phe led to a good correlation between the ratio of extended conformers and biological activity.

Low Molecular Weight, Sequence Based, Collagenase Inhibitors Selectively Block the Interaction Between Collagenase and TIMP (Tissue Inhibitor of Metalloproteinases)

Sequence-based inhibitors of collagenase bearing an hydroxamate group capable of chelating the active site zinc atom were synthesized and tested. The effect of one of these molecules (RP 59794; Ki about 10(-8) M) on the formation of the TIMP: collagenase complex was also tested. RP 59794 blocks complex formation and can partially dissociate established TIMP: collagenase complexes. It exhibits the same stereospecificity in this activity as in its inhibition of collagenase suggesting that TIMP and RP 59794 both interact with the active site region of collagenase.

Local constrained shifty pseudopeptides inhibitors of rasfarnesyl transferase

Abstract Pseudopeptide analogues related to the C-terminal tetrapeptide of ras-protein (Cys-Val-X-Met) were synthesized and evaluated for inhibition of ras farnesyl transferase (FTase). We demonstrate that the introduction of a shifty amino acid related to Cys instead of Cys-Val and a tetrahydroisoquinoline carboxylic acid (TIC) instead of Phe lead to potent inhibitors of FTase on isolated enzyme or on cell based tests. One of the pseudopeptides, conceived as a prodrug, suppressed specifically the ability of ras transformed cells to form colonies in soft agar.

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.

Inhibition of cathepsin D by tripeptides containing statine analogs

Various analogs of statine, a remarkable amino acid component of the protease inhibitor pepstatine, were synthesized and evaluated as tripeptide derivatives for their activity against cathepsin D and HIV-1 protease.

Peptoid mimics of a C2-symmetric inhibitor of the HIV-1 protease

Abstract Compounds II , designed as retro peptoid mimics of a known potent C 2 -symmetric inhibitor I of the HIV protease, were synthesized in solution, using BOP as coupling reagent. They showed no significant inhibitory activity with respect to the HIV-1 protease.

Synthesis of C2-symmetric inhibitors of the HIV-1 protease, with N,N′-substituted ethylenediamide and ethylenediamine linkers.

Abstract Coupling of Z-(L)-phenylalanine with either ethylenediamine or N,N′-dimethylethylenediamine, followed by N-deprotection and either direct coupling with Z-(L)-valine or amide reduction prior to coupling, gave C2-symmetric compounds [Z-Val-Phe-(N(R)CH2-]2 (R = H, CH3) and [Z-Val-Phe(ΨCH2-N)-N(R)CH2-]2 (R= H, CH3, CH2COOH, CH2CH2OH) which were moderately active inhibitors of the HIV-1 protease.

ANTI-HIV ACTIVITY OF N-(2,3-DIHALOGENOPROPYL)- AND N-ALLYL-GLYCINE CONTAINING PENTAPEPTIDES

Abstract A series of peptides containing N -(2,3-dihalopropyl)-glycine or alanine residues has been prepared as potential suicide substrates of the HIV pol -protease or as enzyme-activated prodrugs. Halogenation of unsaturated N -allyl peptide precursors in dichloromethane occurs with participation of a neighboring amide group and leads to halohydrins instead of the expected dihalides. Use of X 2 / LiX/HOAc conditions gives the desired dihalogenated derivatives. These functionalized substrate analogs are not inhibitors of the enzyme. However, Boc-Ala-Phe- N -(2,3-dihalogenopropyl)-Gly-Ile-Val-OMe (halogen= Br and Cl) inhibit the cytopathic effect induced by HIV-1 in CEM cell cultures and the reverse transcriptase activity in cell culture supernatants. The corresponding unsaturated N -allyl precursor also displays an antiviral effect.

From Random Screening of Chemical Libraries to the Optimization of FPP-Competitive Inhibitors of Farnesyltransferase

Together with gene alterations of the p53 tumor suppressor gene, mutations of the ras genes represent the most frequent gene modification umancancers. Ras mutations are found in at least 90% of pancreas, 50% of colon, and 30% of both lung and thyroid cancers (1,2).