Bellavita, Rosa DESIGN & SYNTHESIS OF PEPTIDOMIMETICS AS TOOLBOX TO PROBE EMERGING ANTIMICROBIAL AND ANTICANCER STRATEGIES. [Tesi di dottorato]

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Abstract

Infections caused by ESKAPE pathogens are a huge challenge in both human and veterinary medicine. Among the antimicrobial peptides (AMPs), temporins represent encouraging candidates since they act through a different mode of action from conventional antibiotics. Despite the strong antimicrobial activity, the native Temporin L has not considered an efficacious alternative due to its cytotoxicity. In this scenario, our efforts have been addressed to the improvement of drug-like features of some Temporin L analogues, applying several synthetic approaches spanning from local modification and conformational constraints. Specifically, we performed local modifications consisting of the incorporation of D-amino acids or "decorated prolines" featured by appropriate functional groups (polar-, positively charged-, aliphatic- and aromatic groups) and lipidation strategy in order to improve antimicrobial activity and to preserve low cytotoxicity. In addition, we probed the correlation between alpha-helix secondary structure and antimicrobial activity using different side-chain to side-chain cyclization strategies. In particular, lactamization, the formation of disulfide bridge between cysteines, triazole formation by CuAAC click chemistry reaction, and ring closing metathesis were used to stabilize alpha-helical conformation and to increase the biological activity. Thanks to the application of these several synthetic strategies, we discovered novel Temporin L analogues with a high therapeutic index that have shown characteristics desired to be good candidates in the development of novel antimicrobial agents for topical applications.

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