Investigation of the Role of Hydrophobic Amino Acids on the Structure-Activity Relationship in the Antimicrobial Venom Peptide Ponericin L1.

Venom mixtures from insects, reptiles, and mollusks have long been a source of bioactive peptides which often have alternative uses as therapeutics. While these molecules act in numerous capacities, there have been many venom components that act on the target cells through membrane disruptive mechanisms. These peptides have long been of interest as potential antimicrobial peptide platforms, but the inherent cytotoxicity of venom peptides often results in poor therapeutic potential. Despite this, efforts are ongoing to identify and characterize venom peptide which exhibit high antimicrobial activity with low cytotoxicity and modify these to further enhance the efficacy while reducing toxicity. One example is ponericin L1 from Neoponera goeldii which has been demonstrated to have good antimicrobial activity and low in vitro cytotoxicity. The L1 sequence was modified by uniformly replacing the native hydrophobic residues with either Leu, Ile, Phe, Ala, or Val. Spectroscopic and microbiological approaches were employed to investigate how the amino acid sequence changes impacted membrane interaction, secondary structure, and antimicrobial efficacy. The L1 derivatives showed varying degrees of bilayer interaction, in some cases driven by bilayer composition. Several of the variants exhibited enhanced antimicrobial activity compared to the parent strain, while others lost all activity. Interestingly, the variant containing Val lost all antimicrobial activity and ability to interact with bilayers. Taken together the results indicate that peptide secondary structure, amino acid composition, and hydrophobicity all play a role in peptide activity, although this is a delicate balance that can result in non-specific binding or complete loss of activity if specific amino acids are incorporated.