Hunter-killer peptide (HKP) for targeted therapy.

Hunter-killer peptides (HKPs) are short chimeric molecules (∼20 amino acids) consisting of two functional domains: a “targeting” domain (5-10 amino acids) that facilitates receptormediated binding and internalization into the cytosol of targeted cells and a proapoptotic domain (∼14 amino acids) designed to be nontoxic outside cells but toxic when internalized into targeted cells by the disruption of mitochondrial membranes. HKPs have shown promise as therapeutic agents in animal models of several human diseases. HKPs such as HKP-1, with the amino acid sequence NH2-c(CNGRC)-GG-D(KLAKLAK)2COOH (1) (which includes a cyclic disulfide bridge between the cysteine residues), are targeted to the angiogenic vasculature of tumors and have strong anticancer activity in models of breast and prostate cancer, reducing tumor volume and metastasis and prolonging survival. HKPs targeted to normal prostate vasculature reduce the size of the prostate gland and have a strong anticancer effect in a transgenic adenocarcinoma of the mouse prostate model (TRAMP). HKPs targeted to the synovial vasculature have strong anti-inflammatory effects in a mouse model of collagen-induced arthritis. Finally, HKPs targeted to the normal blood vessels that feed fat deposits decrease obesity in a transgenic mouse model of obesity. A new generation of HKPs currently under development holds the promise of bringing this class of therapeutic agents from the bench to the clinic.

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