Antimicrobial activity and protease stability of peptides containing fluorinated amino acids.
Selective fluorination of peptides results in increased chemical and thermal stability with simultaneously enhanced hydrophobicity. We demonstrate here that fluorinated derivatives of two host defense antimicrobial peptides, buforin and magainin, display moderately better protease stability while retaining, or exhibiting significantly increased bacteriostatic activity. Four fluorinated analogues in the buforin and two in the magainin series were prepared and analyzed for (1) their ability to resist hydrolytic cleavage by trypsin; (2) their antimicrobial activity against both gram-positive and gram-negative bacterial strains; and (3) their hemolytic activity. All but one fluorinated peptide (M2F5) showed retention, or significant enhancement, of antimicrobial activity. The peptides also showed modest increases in protease resistance, relative to the parent peptides. Only one of the six fluorinated peptides (BII1F2) was degraded by trypsin at a slightly faster rate than the parent peptide. Hemolytic activity of peptides in the buforin series was essentially null, while fluorinated magainin analogues displayed an increase in hemolysis compared to the parent peptides. These results suggest that fluorination may be an effective strategy to increase the stability of biologically active peptides where proteolytic degradation limits therapeutic value.
Department of Chemistry, Tufts University, Medford, Massachusetts 02155, USA.
He
H
Meng
Krishna
K
Kumar
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000187:drug effects; D002942:Circular Dichroism; D010450:Endopeptidases / Q000378:metabolism*; D004912:Erythrocytes / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D005461:Fluorine / Q000737:chemistry*; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D014461:Ultracentrifugation
D000596:Amino Acids; D000900:Anti-Bacterial Agents; D010455:Peptides; D005461:Fluorine; D010450:Endopeptidases