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Antimicrobial Peptide Mimetics Based on a Diphenylacetylene Scaffold: Synthesis, Conformational Analysis, and Activity
Author(s) -
Peacock Hayden,
Henriques Sónia Troeira,
Benfield Aurélie H.,
Elliott Alysha G.,
Luo Jinghui,
Luccarelli James,
Nagano Masanobu,
Craik David J.,
Hamilton Andrew D.
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000474
Subject(s) - diphenylacetylene , chemistry , amphiphile , peptide , antimicrobial , combinatorial chemistry , antimicrobial peptides , antibacterial activity , peptide synthesis , membrane , stereochemistry , biochemistry , organic chemistry , bacteria , biology , catalysis , genetics , polymer , copolymer
Mimics of natural antimicrobial peptides are promising compounds to fight the rising threat of multi‐drug resistant bacteria. Here we report the design, synthesis and conformational analysis of a new class of antimicrobial peptide mimetics incorporating a diphenylacetylene scaffold. Within a small set of compounds, we observe a correlation between amphiphilicity, the efficiency of partitioning into negatively charged membranes and antibacterial activity. The most amphiphilic compound, which contains four isoleucine residues and four lysine residues, displays species‐selective antibacterial activity (most active against Bacillus subtills ) and low haemolytic activity. Solution‐phase conformational analysis of this compound indicates that a defined structure is adopted in the presence of negatively charged phospholipid membranes and aqueous 2,2,2‐trifluoroethanol but not in water. A conformation model indicates that the cationic and hydrophobic functional groups are segregated. These results may inform the development of highly selective antimicrobial peptide mimetics for therapeutic applications.