The consideration of indolicidin modification to balance its hemocompatibility and delivery efficiency

Indolicidin (IL) is an antimicrobial peptide (AMP), which has been utilized as a cell penetrating peptide (CPP) for drug delivery. However, the hemolysis restricts its clinical application. Therefore, we investigated the delivery efficiency and hemocompatibility of IL and its derivatives. The transportation of fluorophore to NIH/3T3 cells could be improved either by in accompany with these peptides or in the form of peptide-conjugates. The hydrophobicity scales of these peptides were calculated according to their residues, which were compared to their effects on hemolysis as well as cell uptake efficiency. The results suggested that the cell penetrability of IL and its derivatives was related to their hydrophobicity scales based on the octanol-interface scale (ΔG_oct-if), whereas their hemolysis levels depended on the hydrophobicity scales based on interface (ΔG_wif). Consequently, we designed two peptides, IL-R57F89 and SAP10, to validate the correlation. These two peptides had similar ΔG_wif; however, the ΔG_oct-if of SAP10 was much higher than that of IL-K7F89. Both IL-R57F89 and SAP10 demonstrated extremely low hemolysis. Compared to the limit cell uptake of SAP10, IL-R57F89 greatly promoted the delivery efficiency. These results were consistent to our prediction, suggesting that hydrophobicity scales should be a useful preliminary guidance for AMP-derived CPP design.