BOSTON—Antimicrobial peptides are being increasingly viewed as an attractive therapeutic option, but their middling activity and sensitivity to proteases has kept them from moving far down the drug pipeline. Researchers at Tufts University recently tried to incorporate fluorinated amino acid analogues to address these problems. They presented their results in JACS.
The researchers focused their efforts on the peptides buforin II (BII) and magainin II amide (M2), which exert bactericidal activity at low micromolar concentrations but have very different modes of action. They generated a series of peptide analogues by replacing one or more hydrophobic peptide residues with hexafluoroleucine and noted that the antimicrobial activity of most analogues improved over the parent peptide. They also noted that at least for the BII analogues, the peptides offered the same low hemolytic activity of BII, showing the peptides were quite specific for bacterial cells and not all cells.
The researchers then tested the analogues against protease digestion by trypsin and found that all fluorinated peptides were more resistant to digestion than BII or M2. The scientists believe that this is due to steric hinderance of the protease by the bulky hexafluoroleucine. "These results," write the researchers, "suggest that fluorination may be an effective strategy to increase the stability of biologically active peptides where proteolytic degradation limits therapeutic value."
