Novel analogues of Temporin L and their potential therapeutic application

Antimicrobial peptides (AMPs) are produced from almost all living species and are characterized bya fast-acting and efficient defence against microbial pathogens. The large interest aroused by thesepeptides is due to their target, that is the bacterial membrane, in which they can accumulate, increasingits permeability and causing the death of the microbes.[1] Though this way of action, the formationof resistant strains is much less likely to be induced, that happens using traditional antibiotics. Theamphibian Temporins are the largest family of AMPs, consisting of more than 100 peptides. As mostof the antimicrobial peptides, Temporins adopt an amphipathic a-helical secondary structure in ahydrophobic environment. Usually this condition is responsible for their antimicrobial activity, but forthe most potent Temporin L (TL) this property seems to be better correlated to the hemolytic/cytolyticactivity. For this reason, and with the aim to improve its therapeutic index, several SAR studies havebeen made on the sequence of TL. Recently, we have obtained a TL derivatives, TL-34, practicallydevoid of cytolytic effects in vitro and which preserves the antimicrobial activity mainly toward Gram+ bacteria.[2] In this work, to further study the importance of the C-terminal region of Temporin L,we have synthesized a novel series of TL-34 analogues, in which we replaced the Gly10 residue withseveral amino acids characterized by a different hydrophilic/lipophilic balance and by their ability tomodify the secondary structure of the sequence. These peptides were evaluated on a panel of bacterialstrains, both Gram + and Gram - and on some bacterial strains isolated from human skin, resistanttoward conventional antibiotics. Furthermore, the cytotoxicity on human keratinocytes was evaluatedto establish their potential therapeutic application.