Synthesis and conformational analysis of peptide inhibitors of farnesyltransferase

Gerardo Byk; Yves Lelievre; Marc Duchesne; François F. Clerc; Daniel Scherman; Jean Dominique Guitton

doi:10.1016/s0968-0896(96)00210-6

Synthesis and conformational analysis of peptide inhibitors of farnesyltransferase

Gerardo Byk, Yves Lelievre, Marc Duchesne, François F. Clerc, Daniel Scherman, Jean Dominique Guitton

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

Abstract

Darnesylation 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.

Original language	English
Pages (from-to)	115-124
Number of pages	10
Journal	Bioorganic and Medicinal Chemistry
Volume	5
Issue number	1
DOIs	https://doi.org/10.1016/s0968-0896(96)00210-6
State	Published - Jan 1997
Externally published	Yes

Bibliographical note

Funding Information:
This work was carriedo ut as a part of the 'Bio Avenir' programs upportebdy Rh6ne Poulencw, ith the participation of the French Ministries of Research and IndustryW. e thankD r Marc Vuilhorgnea nd his staff, in particular:S erge Sable, Mireille Robin, Martin Danzer, Laurence Ridoux and Bertrand Monegier from the StructuralA nalysis Departmenot f Rh6ne Poulenc Rorer for structural analysis and to Dr TamaraB yk for criticalr eedingo f this manuscript.

Funding

This work was carriedo ut as a part of the 'Bio Avenir' programs upportebdy Rh6ne Poulencw, ith the participation of the French Ministries of Research and IndustryW. e thankD r Marc Vuilhorgnea nd his staff, in particular:S erge Sable, Mireille Robin, Martin Danzer, Laurence Ridoux and Bertrand Monegier from the StructuralA nalysis Departmenot f Rh6ne Poulenc Rorer for structural analysis and to Dr TamaraB yk for criticalr eedingo f this manuscript.

Funders	Funder number
French Ministries of Research and IndustryW
Rh6ne Poulencw

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10.1016/s0968-0896(96)00210-6

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title = "Synthesis and conformational analysis of peptide inhibitors of farnesyltransferase",

abstract = "Darnesylation 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.",

author = "Gerardo Byk and Yves Lelievre and Marc Duchesne and Clerc, {Fran{\c c}ois F.} and Daniel Scherman and Guitton, {Jean Dominique}",

note = "Funding Information: This work was carriedo ut as a part of the 'Bio Avenir' programs upportebdy Rh6ne Poulencw, ith the participation of the French Ministries of Research and IndustryW. e thankD r Marc Vuilhorgnea nd his staff, in particular:S erge Sable, Mireille Robin, Martin Danzer, Laurence Ridoux and Bertrand Monegier from the StructuralA nalysis Departmenot f Rh6ne Poulenc Rorer for structural analysis and to Dr TamaraB yk for criticalr eedingo f this manuscript.",

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doi = "10.1016/s0968-0896(96)00210-6",

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AU - Duchesne, Marc

AU - Clerc, François F.

AU - Scherman, Daniel

AU - Guitton, Jean Dominique

N1 - Funding Information: This work was carriedo ut as a part of the 'Bio Avenir' programs upportebdy Rh6ne Poulencw, ith the participation of the French Ministries of Research and IndustryW. e thankD r Marc Vuilhorgnea nd his staff, in particular:S erge Sable, Mireille Robin, Martin Danzer, Laurence Ridoux and Bertrand Monegier from the StructuralA nalysis Departmenot f Rh6ne Poulenc Rorer for structural analysis and to Dr TamaraB yk for criticalr eedingo f this manuscript.

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AB - Darnesylation 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.

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Synthesis and conformational analysis of peptide inhibitors of farnesyltransferase

Abstract

Bibliographical note

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