Biaryl amino acid templates in place of D-Pro-L-Pro in cyclic beta-hairpin cationic antimicrobial peptidomimetics.
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.
Srinivas
Nityakalyani
N
Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
Moehle
Kerstin
K
Abou-Hadeed
Khaled
K
Obrecht
Daniel
D
Robinson
John A
JA
D000596:Amino Acids / Q000737:chemistry*; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D004151:Dipeptides / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry; D011487:Protein Conformation
D000596:Amino Acids; D023181:Antimicrobial Cationic Peptides; D004151:Dipeptides; D010456:Peptides, Cyclic; C448039:prolyl-proline