Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 52, Issue 10, Pages 3293-3299Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm900178n
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Funding
- University of Toronto, the Canadian Foundation for Innovation
- Ontario Ministry of Innovation
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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 LC50 value 100-fold lower than the parent compound. Importantly, the peptides maintain their potency when made cell-type specific.
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