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

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.