Use of parallel synthesis to probe structure-activity relationships among 12-helical beta-peptides: evidence of a limit on antimicrobial activity.
We report structure-activity trends among helix-forming beta-amino acid oligomers that are intended to mimic alpha-helical host-defense peptides. Parallel synthesis of two small, focused beta-peptide libraries allowed us to identify relatively short (11-residue) beta-peptides that display antimicrobial activity. These beta-peptides exhibit selectivity for bacteria relative to human red blood cells. A large hydrophobic helical surface is necessary for antimicrobial activity. Longer analogues (16 residues) of the most active library members were prepared and evaluated. Some of these longer beta-peptides showed very good antimicrobial activity, but none was more active than a previously reported beta-peptide [Porter, E. A.; Wang, X.; Lee, H.-S.; Weisblum, B.; Gellman, S. H. Nature 2000, 404, 565]. The extensive literature on alpha-helical host-defense peptides and related alpha-peptides indicates that such molecules are seldom active at concentrations below 1 microg/mL, and our results suggest that amphiphilic helical beta-peptides are subject to a comparable limit.
Porter
Emilie A
EA
Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706, USA.
Weisblum
Bernard
B
Gellman
Samuel H
SH
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008969:Molecular Sequence Data; D019151:Peptide Library; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D019151:Peptide Library