Targeted Vpr-derived peptides reach mitochondria to induce apoptosis of alphaVbeta3-expressing endothelial cells

Cell Death Differ. 2007 Mar;14(3):422-35. doi: 10.1038/sj.cdd.4402018. Epub 2006 Aug 4.


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.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis
  • Cell Survival
  • Dose-Response Relationship, Drug
  • Endothelial Cells / metabolism
  • Endothelial Cells / physiology*
  • Gene Products, vpr / pharmacokinetics*
  • Gene Products, vpr / pharmacology
  • Humans
  • Integrin alphaVbeta3 / metabolism*
  • Lysosomes / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mitochondria / metabolism*
  • Mitochondrial Membranes / metabolism
  • Molecular Sequence Data
  • Peptides / pharmacokinetics*
  • Peptides / pharmacology
  • Permeability


  • Gene Products, vpr
  • Integrin alphaVbeta3
  • Peptides