Antimicrobial activities of heparin-binding peptides.

Antimicrobial peptides are effector molecules of the innate immune system. We recently showed that the human antimicrobial peptides alpha-defensin and LL-37 bind to glycosaminoglycans (heparin and dermatan sulphate). Here we demonstrate the obverse, i.e. structural motifs associated with heparin affinity (cationicity, amphipaticity, and consensus regions) may confer antimicrobial properties to a given peptide. Thus, heparin-binding peptides derived from laminin isoforms, von Willebrand factor, vitronectin, protein C inhibitor, and fibronectin, exerted antimicrobial activities against Gram-positive and Gram-negative bacteria. Similar results were obtained using heparin-binding peptides derived from complement factor C3 as well as consensus sequences for heparin-binding (Cardin and Weintraub motifs). These sequence motifs, and additional peptides, also killed the fungus Candida albicans. These data will have implications for the search for novel antimicrobial peptides and utilization of heparin-protein interactions should be helpful in the identification and purification of novel antimicrobial peptides from complex biological mixtures. Finally, consensus regions may serve as templates for de novo synthesis of novel antimicrobial molecules

Binding of a de novo designed peptide to specific glycosaminoglycans

AbstractThe binding of glycosaminoglycans to a synthetic peptide (SKAQKAQAKQAKQAQKAQKAQAKQAKQW–CONH2), consisting of a hybrid consensus heparin binding sequence, is studied using circular dichroism, fluorescence anisotropy and nuclear magnetic resonance techniques. The results unveil certain novel features, most importantly, the peptide binds preferentially to iduronic acid containing glycosaminoglycans and the dissociation constant for the peptide–heparin complex was found to be 30 nM. Interestingly, higher order intermolecular association(s)/aggregation was not observed, especially at saturating concentrations of the ligand. The helical structure of the peptide backbone, induced upon binding to a particular glycosaminoglycan is directly related to their binding affinity. In our opinion, studies on such unconventional hybrid peptide sequences containing low density basic amino acid residues would lead to the design of sequence specific glycosaminoglycan binding peptides