Structure-based design of potent histation analogues

摘要

Conformational studies of human salivary peptide,histatin 3(Hst3),were performed by nuclear magnetic resonance (NMR)and circular dichrosim (CD) spectroscopy in a membrane-mimicking environment.The structural informationthat was obtained was used in the design of peptide analogues with improved antifungal activity.In the presence of increasig concentrations of L-#alpha#-dimyristoyphosphatidylcholine (L-#alpha#-DMPC)lipid vesicles,a dramatic increase in a minimum at 198nm is observed in the CD spectra of Hst3.The NMR data of Hst3 in the presence of L-#beta#-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 incoporated 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.