Enhanced serum proteolysis resistance of cell-penetrating peptides

Aim: Before starting preclinical studies, we have analyzed the integrity in serum of DPT-C9h, a promising therapeutic peptide, and performed modifications in order to improve its stability. Materials & methods: Mutant peptides exchanging arginine 8 for either lysine, asparagine or alanine were synthesized and compared with the parental peptide. Results: All mutants clearly improved peptide stability while keeping their functional activity. PK studies showed an enhanced stability, being Mut3DPT-C9h the most promising candidate. Biodistribution studies demonstrate that the modified peptide is able to reach the targeted tumor and accumulate there at higher concentration than the parental peptide. Discussion: Small modifications in the peptide sequence result in improvements allowing the selection of better candidates for preclinical studies.