Synthesis and biological characterisation of targeted pro-apoptotic peptide.
We report herein the synthesis and in vitro assay of new, multimeric RGD-peptide conjugates for cell-targeted drug delivery. We generated a peptide scaffold comprising two functional domains, one a tumour blood vessel "homing" motif and the other a programmed cell-death-inducing peptide sequence. RGD peptides were selected to direct the molecular conjugate to alpha(V)beta(3) integrin-containing tumour cells. The pro-apoptotic (Lys-Leu-Ala-Lys-Leu-Ala-Lys)(2) peptide was found to be nontoxic outside cells, but toxic when internalized into targeted cells as it disrupted the mitochondrial membrane. The synthesis of these targeted pro-apoptotic conjugates was carried out by assembling three different units (that is, scaffold, RGD units and pro-apoptotic peptide) through chemoselective ligations. We show that one compound displays significant biological effect in alpha(V)beta(3) integrin-containing tumour cells.
Foillard
Stéphanie
S
Département de Chimie Moléculaire, UMR CNRS-UJF 5250, ICMG FR 2607, 301, rue de la chimie, BP 53, FR 38041 Grenoble Cedex 9, France.
Jin
Zhao-hui
ZH
Garanger
Elisabeth
E
Boturyn
Didier
D
Favrot
Marie-Christine
MC
Coll
Jean-Luc
JL
Dumy
Pascal
P
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002417:Cattle; D002477:Cells / Q000166:cytology / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000138:chemical synthesis / Q000378:metabolism; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013379:Substrate Specificity
D003432:Cross-Linking Reagents; D004337:Drug Carriers; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D010455:Peptides; C047981:arginyl-glycyl-aspartic acid