Biaryl amino acid templates in place of D-Pro-L-Pro in cyclic beta-hairpin cationic antimicrobial peptidomimetics

Org Biomol Chem. 2007 Oct 7;5(19):3100-5. doi: 10.1039/b706370a. Epub 2007 Aug 17.

Abstract

The turn-forming D-Pro-L-Pro template has been frequently used to promote regular beta-hairpin conformations in cyclic protein epitope mimetics. Here the use of three isomeric biaryl templates has been studied as alternatives to D-Pro-L-Pro in the preparation of beta-hairpin peptidomimetics. The o,o'- o,m'- and m,m'-isomers of carboxymethyl- and aminomethyl-substituted biaryl templates have been incorporated into novel macrocyclic mimics of the naturally occurring cationic antimicrobial peptide protegrin I. The presence of the o-carboxymethyl-o'-aminomethyl-biaryl template within the macrocyclic peptide resulted in the appearance of slowly interconverting atropisomers. Although none of the resulting mimetics adopted stable beta-hairpin structures in aqueous solution, they all nevertheless retained a significant antimicrobial activity against Gram positive and Gram negative bacteria. These mimetics provide interesting starting points for an optimization program in the search for potent and novel antimicrobial compounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemistry*
  • Antimicrobial Cationic Peptides / chemical synthesis*
  • Antimicrobial Cationic Peptides / chemistry
  • Chromatography, High Pressure Liquid
  • Circular Dichroism
  • Dipeptides / chemistry*
  • Magnetic Resonance Spectroscopy
  • Peptides, Cyclic / chemical synthesis*
  • Peptides, Cyclic / chemistry
  • Protein Conformation

Substances

  • Amino Acids
  • Antimicrobial Cationic Peptides
  • Dipeptides
  • Peptides, Cyclic
  • prolyl-proline