TY - JOUR
T1 - First-in-Class Cyclic Temporin L Analogue
T2 - Design, Synthesis, and Antimicrobial Assessment
AU - Bellavita, Rosa
AU - Casciaro, Bruno
AU - Di Maro, Salvatore
AU - Brancaccio, Diego
AU - Carotenuto, Alfonso
AU - Falanga, Annarita
AU - Cappiello, Floriana
AU - Buommino, Elisabetta
AU - Galdiero, Stefania
AU - Novellino, Ettore
AU - Grossmann, Tom N.
AU - Mangoni, Maria Luisa
AU - Merlino, Francesco
AU - Grieco, Paolo
N1 - 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.
PY - 2021/8/12
Y1 - 2021/8/12
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.1c01033
DO - 10.1021/acs.jmedchem.1c01033
M3 - Article
C2 - 34296619
AN - SCOPUS:85112392790
SN - 0022-2623
VL - 64
SP - 11675
EP - 11694
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 15
ER -
