Structure-based design of potent histatin analogues.
Conformational studies of human salivary peptide, histatin 3 (Hst3), were performed by nuclear magnetic resonance (NMR) and circular dichroism (CD) spectroscopy in a membrane-mimicking environment. The structural information that was obtained was used in the design of peptide analogues with improved antifungal activity. In the presence of increasing concentrations of L-alpha-dimyristoylphosphatidylcholine (L-alpha-DMPC) lipid vesicles, a dramatic increase in a minimum at 198 nm is observed in the CD spectra of Hst3. The NMR data of Hst3 in the presence of L-alpha-DMPC lipid vesicles reveal the proximity of residues Y(10) and S(20), indicating the existence of a more compact structure. Peptide analogues were designed on the basis of this observation, which incorporated a disulfide bond to stabilize an extended loop in this region of the sequence. One of these, peptide 4, was 100 times more potent than Hst5 against Saccharomyces cerevisiae cells. Conformational analysis of peptide 4 revealed a looped structure with charged residues protruding on the outside surface, while a combination of aromatic residues and histidines are packed into an internal core.
Brewer
Dyanne
D
Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry, Department of Chemistry, University of Waterloo, Waterloo, Ontario N2L 3G1, Canada.
Lajoie
Gilles
G
D000595:Amino Acid Sequence; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002942:Circular Dichroism; D004134:Dimyristoylphosphatidylcholine / Q000737:chemistry; D054808:Histatins; D008081:Liposomes; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010452:Peptide Biosynthesis; D011487:Protein Conformation; D011506:Proteins / Q000138:chemical synthesis* / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000254:growth & development; D012471:Salivary Proteins and Peptides / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000935:Antifungal Agents; C068075:HTN3 protein, human; D054808:Histatins; D008081:Liposomes; D011506:Proteins; D012471:Salivary Proteins and Peptides; D004134:Dimyristoylphosphatidylcholine