First-in-Class Cyclic Temporin L Analogue: Design, Synthesis, and Antimicrobial Assessment

Rosa Bellavita, Bruno Casciaro, Salvatore Di Maro, Diego Brancaccio, Alfonso Carotenuto, Annarita Falanga, Floriana Cappiello, Elisabetta Buommino, Stefania Galdiero, Ettore Novellino, Tom N. Grossmann, Maria Luisa Mangoni, Francesco Merlino*, Paolo Grieco

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

The pharmacodynamic and pharmacokinetic properties of bioactive peptides can be modulated by introducing conformational constraints such as intramolecular macrocyclizations, which can involve either the backbone and/or side chains. Herein, we aimed at increasing the α-helicity content of temporin L, an isoform of an intriguing class of linear antimicrobial peptides (AMPs), endowed with a wide antimicrobial spectrum, by the employment of diverse side-chain tethering strategies, including lactam, 1,4-substituted [1,2,3]-triazole, hydrocarbon, and disulfide linkers. Our approach resulted in a library of cyclic temporin L analogues that were biologically assessed for their antimicrobial, cytotoxic, and antibiofilm activities, leading to the development of the first-in-class cyclic peptide related to this AMP family. Our results allowed us to expand the knowledge regarding the relationship between the α-helical character of temporin derivatives and their biological activity, paving the way for the development of improved antibiotic cyclic AMP analogues.

Original languageEnglish
Pages (from-to)11675-11694
Number of pages20
JournalJournal of medicinal chemistry
Volume64
Issue number15
Early online date23 Jul 2021
DOIs
Publication statusPublished - 12 Aug 2021

Bibliographical note

Funding Information:
This study was partially supported by the grants from Sapienza University (Project No. RM11916B6A28725C to M.L.M.).

Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society.

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

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