Roles of Salt and Conformation in the Biological and Physicochemical Behavior of Protegrin-1 and Designed Analogues: Correlation of Antimicrobial, Hemolytic, and Lipid Bilayer-Perturbing Activities
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- 作者：Jonathan R. Lai ; Raquel F. Epand ; Bernard Weisblum ; Richard M. Epand ; Samuel H. Gellman
- 刊名：Biochemistry
- 出版年：2006
- 出版时间：December 26, 2006
- 年：2006
- 卷：45
- 期：51
- 页码：15718 - 15730
- 全文大小：277K
- 年卷期：v.45,no.51(December 26, 2006)
- ISSN：1520-4995
文摘
Protegrins are short (16-18 residues) cationic peptides from porcine leukocytes that displaypotent, broad-spectrum antimicrobial activity. Protegrin-1 (PG-1), one of five natural homologues, adoptsa rigid 
fchars/beta2.gif" BORDER=0 ALIGN="middle">-hairpin structure that is stabilized by two disulfide bonds. We have previously employed theprinciples of fchars/beta2.gif" BORDER=0 ALIGN="middle">-hairpin design to develop PG-1 variants that lack disulfide bonds but nevertheless displaypotent antimicrobial activity [Lai, J. R., Huck, B. R., Weisblum, B., and Gellman, S. H. (2002) Biochemistry41, 12835-12842.]. The activity of these disulfide-free variants, however, is attenuated in the presenceof salt, and the activity of PG-1 itself is not. Salt-induced inactivation of host-defense peptides, such ashuman defensins, is thought to be important in some pathological situations (e.g., cystic fibrosis), and thevariation in salt-sensitivity among our PG-1 analogues offers a model system with which to explore theorigins of these salt effects. We find that the variations in antimicrobial activity among our peptides arecorrelated with the folding propensities of these molecules and with the extent to which the peptidesinduce leakage of contents from synthetic liposomes. Comparable correlations were observed betweenfolding and hemolytic activity. The extent to which added salt reduces antimicrobial activity parallels salteffects on vesicle perturbation, which suggests that the biological effects of high salt concentrations arisefrom modulation of peptide-membrane interactions.
fchars/beta2.gif" BORDER=0 ALIGN="middle">-hairpin structure that is stabilized by two disulfide bonds. We have previously employed theprinciples of fchars/beta2.gif" BORDER=0 ALIGN="middle">-hairpin design to develop PG-1 variants that lack disulfide bonds but nevertheless displaypotent antimicrobial activity [Lai, J. R., Huck, B. R., Weisblum, B., and Gellman, S. H. (2002) Biochemistry41, 12835-12842.]. The activity of these disulfide-free variants, however, is attenuated in the presenceof salt, and the activity of PG-1 itself is not. Salt-induced inactivation of host-defense peptides, such ashuman defensins, is thought to be important in some pathological situations (e.g., cystic fibrosis), and thevariation in salt-sensitivity among our PG-1 analogues offers a model system with which to explore theorigins of these salt effects. We find that the variations in antimicrobial activity among our peptides arecorrelated with the folding propensities of these molecules and with the extent to which the peptidesinduce leakage of contents from synthetic liposomes. Comparable correlations were observed betweenfolding and hemolytic activity. The extent to which added salt reduces antimicrobial activity parallels salteffects on vesicle perturbation, which suggests that the biological effects of high salt concentrations arisefrom modulation of peptide-membrane interactions.