Selectivity Modulation and Structure of α/aza-β 3 Cyclic Antimicrobial Peptides

Chemistry. 2018 Apr 20;24(23):6191-6201. doi: 10.1002/chem.201800152. Epub 2018 Mar 26.

Abstract

Potent and selective antimicrobial cyclic pseudopeptides (ACPPs) mixing α- and aza-β3 -amino acids were developed. Cyclopseudopeptide sequences were designed to investigate the impact of some intrinsic molecular parameters on their biological activities. Fine changes in the nature of the side chains strongly modulated the selectivity of the ACPPs with regard to hemolysis versus antimicrobial activity. The conformational preference of such compounds in various media was extensively studied, and the typical structure of cyclic α/aza-β3 -pseudopeptides is described for the first time. Interestingly, such scaffolds are stabilized by successive inverse γ- and N-N turns (hydrazino turns), a unique feature due to the aza-β3 residues. The α-amino acid side chains form a cluster on one face of the ring, while the aza-β3 -amino acid side chains are projected around the ring in the equatorial orientation. Such structural data are particularly valuable to fine-tune the bioactivity of these ACPPs by a structure-based approach.

Keywords: antibiotics; aza amino acids; cyclic peptides; peptides; peptidomimetics.

MeSH terms

  • Amino Acid Sequence
  • Amino Acids / chemistry
  • Anti-Bacterial Agents / chemistry
  • Anti-Infective Agents / chemistry
  • Antimicrobial Cationic Peptides / chemistry*
  • Aza Compounds / chemistry
  • Hemolysis
  • Microbial Sensitivity Tests
  • Molecular Conformation
  • Peptides / chemistry
  • Peptides, Cyclic / chemistry*
  • Protein Structure, Secondary
  • Structure-Activity Relationship

Substances

  • Amino Acids
  • Anti-Bacterial Agents
  • Anti-Infective Agents
  • Antimicrobial Cationic Peptides
  • Aza Compounds
  • Peptides
  • Peptides, Cyclic