Tryptic Stability and Antimicrobial Activity of the Derivatives of Polybia-CP with Fine-Tuning Modification in the Side Chain of Lysine

Antimicrobial peptides (AMPs) were believed to be a class of promising antimicrobials to combat the increasing resistant microbes. However, AMPs could be easily degraded by endogenous proteases, which limited their clinic use. Considering that lysine is the only one cationic amino acid residue in polybia-CP which were related to the cleavage of trypsin like serine protease's digestion, we introduced lysine's mimics which kept the key function group side chain -NH2 and only varied the methylene chains in the sequence of polybia-CP to investigate the effect of the introduction of non-proteinogenic amino acids on the activity and stability of antimicrobial peptides. In addition, two analogs in which lysine were substituted by the other two proteinogenic cationic amino acids arginine and histidine also were synthesized to evaluate the effect of fine tuning the function group in lysine on its antimicrobial activity and stability. We found that the introduction of amino acids with shortened side chain length of lysine could enhance the trypsin resistance of the derivatives of polybia-CP, while maintain the same or comparable antimicrobial activity with the parent peptide. In addition, while lysine was substituted by histidine, His-CP demonstrated comparable antimicrobial activity and dramatically improved trypsin resistance. Although the analog exhibited excellent antimicrobial activity while lysine was substituted by Arginine residue (Arg-CP), its enzymatic stability was almost the same as its parent peptide. These results suggest that the fine-tuning of side chain of lysine may offer a promising strategy to improve the tryptic stability and retain the antimicrobial activity of antimicrobial peptide.