Engineered apoptosis-inducing peptides with enhanced mitochondrial localization and potency

J Med Chem. 2009 May 28;52(10):3293-9. doi: 10.1021/jm900178n.


Apoptosis-inducing peptides that trigger mitochondrial disruption are a popular tool in pharmaceutical and anticancer research. While useful, their potencies are low, which impedes further development of drugs based on these sequences. Here, we describe an effort to engineer the intracellular localization and activity of a peptide with known anticancer activity, D-(KLAKLAK)(2), to improve potency by increasing the specificity of the peptide for mitochondria and enhancing disruption of this organelle. The engineered peptides are significantly more toxic to a wide variety of cancer cell lines, with the best analogue exhibiting a LC(50) value 100-fold lower than the parent compound. Importantly, the peptides maintain their potency when made cell-type specific.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Humans
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacokinetics
  • Oligopeptides / pharmacology*
  • Protein Engineering


  • Antineoplastic Agents
  • Oligopeptides