title: Targeted Vpr-derived peptides reach mitochondria to induce apoptosis of alphaVbeta3-expressing endothelial cells.
abstract: The HIV-1 encoded apoptogenic protein Vpr induces mitochondrial membrane permeabilization (MMP) via interactions with the voltage-dependent anion channel (VDAC) and the adenine nucleotide translocator (ANT). We have designed a peptide, TEAM-VP, composed of two functional domains, one a tumor blood vessel RGD-like 'homing' motif and the other an MMP-inducing sequence derived from Vpr. When added to isolated mitochondria, TEAM-VP interacts with ANT and VDAC, reduces oxygen consumption and overcomes Bcl-2 protection to cause inner and outer MMP. TEAM-VP specifically recognizes cell-surface expressed alpha(V)beta(3) integrins, internalizes, temporarily localizes to lysosomes and progressively co-distributes with the mitochondrial compartment with no sign of lysosomal membrane permeabilization. Finally TEAM-VP reaches mitochondria of angiogenic endothelial cells to induce mitochondrial fission, dissipation of the mitochondrial transmembrane potential (DeltaPsi(m)), cytochrome c release and apoptosis hallmarks. Hence, this chimeric peptide constitutes the first example of a virus-derived mitochondriotoxic compound as a candidate to kill selectively tumor neo-endothelia.
authors.affiliation: Theraptosis Research Laboratory, THERAPTOSIS S.A., 28 rue du Dr. Roux, Paris cedex 15, France.
authors.forename: A
authors.initials: A
authors.lastname: Borgne-Sanchez
authors.forename: S
authors.initials: S
authors.lastname: Dupont
authors.forename: A
authors.initials: A
authors.lastname: Langonné
authors.forename: L
authors.initials: L
authors.lastname: Baux
authors.forename: H
authors.initials: H
authors.lastname: Lecoeur
authors.forename: D
authors.initials: D
authors.lastname: Chauvier
authors.forename: M
authors.initials: M
authors.lastname: Lassalle
authors.forename: O
authors.initials: O
authors.lastname: Déas
authors.forename: J-J
authors.initials: JJ
authors.lastname: Brière
authors.forename: M
authors.initials: M
authors.lastname: Brabant
authors.forename: P
authors.initials: P
authors.lastname: Roux
authors.forename: C
authors.initials: C
authors.lastname: Péchoux
authors.forename: J-P
authors.initials: JP
authors.lastname: Briand
authors.forename: J
authors.initials: J
authors.lastname: Hoebeke
authors.forename: A
authors.initials: A
authors.lastname: Deniaud
authors.forename: C
authors.initials: C
authors.lastname: Brenner
authors.forename: P
authors.initials: P
authors.lastname: Rustin
authors.forename: L
authors.initials: L
authors.lastname: Edelman
authors.forename: D
authors.initials: D
authors.lastname: Rebouillat
authors.forename: E
authors.initials: E
authors.lastname: Jacotot
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology*; D016336:Gene Products, vpr / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D008969:Molecular Sequence Data; D010455:Peptides / Q000493:pharmacokinetics* / Q000494:pharmacology; D010539:Permeability
chemical_list: D016336:Gene Products, vpr; D039302:Integrin alphaVbeta3; D010455:Peptides