Improved solid-phase synthesis of alpha,alpha-dialkylated amino acid-rich peptides with antimicrobial activity.
A homologous series of nonapeptides and their acetylated versions were successfully prepared using solid-phase synthetic techniques. Each nonapeptide was rich in alpha,alpha-dialkylated amino acids [one 4-aminopiperidine-4-carboxylic acid (Api) and six alpha-aminoisobutyric acid (Aib) residues] and also included lysines or lysine analogs (two residues). The incorporation of the protected dipeptide 9-fluorenylmethyloxycarbonyl (Fmoc)-Aib-Aib-OH improved the purity and overall yields of these de novo designed peptides. The helix preference of each nonapeptide was investigated in six different solvent environments, and each peptide's antimicrobial activity and cytotoxicity were studied. The 3(10)-helical, amphipathic design of these peptides was born out most prominently in the N-terminally acetylated peptides. Most of the peptides exhibited modest activity against Escherichia coli and no activity against Staphylococcus aureus. The nonacetylated peptides (concentrations < or =100 microM) and the acetylated peptides (concentrations < or = 200 microM) did not exhibit any significant cytotoxicity with normal (nonactivated) murine macrophages.
Haynes
S R
SR
Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803, USA.
Hagins
S D
SD
Juban
M M
MM
Elzer
P H
PH
Hammer
R P
RP
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002478:Cells, Cultured; D002942:Circular Dichroism; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D010446:Peptide Fragments; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011384:Proinsulin; D013211:Staphylococcus aureus / Q000187:drug effects
C482904:9-fluorenylmethoxycarbonyl-arginyl-glycyl-isoleucyl-valyl-glutamyl-glutaminyl-cysteinyl-cysteinyl-threonyl-serine; D000900:Anti-Bacterial Agents; D010446:Peptide Fragments; D010455:Peptides; D011384:Proinsulin