Antimicrobial Peptide Mimetics Based on a Diphenylacetylene Scaffold: Synthesis, Conformational Analysis, and Activity

Hayden Peacock, Sónia Troeira Henriques, Aurélie H. Benfield, Alysha G. Elliott, Jinghui Luo, James Luccarelli, Masanobu Nagano, David J. Craik, Andrew D. Hamilton

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalChemMedChem
DOIs
StateAccepted/In press - 2020

Keywords

  • Antimicrobial peptides
  • Membrane-active compounds
  • Peptidomimetics

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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    Peacock, H., Henriques, S. T., Benfield, A. H., Elliott, A. G., Luo, J., Luccarelli, J., Nagano, M., Craik, D. J., & Hamilton, A. D. (Accepted/In press). Antimicrobial Peptide Mimetics Based on a Diphenylacetylene Scaffold: Synthesis, Conformational Analysis, and Activity. ChemMedChem. https://doi.org/10.1002/cmdc.202000474