Linked Life Data

10821683

Source:http://linkedlifedata.com/resource/pubmed/id/10821683

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
20
pubmed:dateCreated
2000-6-21
pubmed:abstractText
The amphipathic alpha-helical structure is considered to be a prerequisite for the lytic activity of a large group of cytolytic peptides. However, despite numerous studies on the contribution of various parameters to their structure and activity, the importance of linearity has not been examined. In the present study we functionally and structurally characterized a linear amphipathic alpha-helical peptide (wt peptide), its diastereomer, and cyclic analogues of both. Using analogues with the same sequence of hydrophobic and positively charged amino acids, but with different propensities to form a helical structure, we were able to examine the contribution of linearity to helix formation, bilogical function, and membrane binding and permeation. Importantly, we found that cyclization increases the selectivity between bacteria and human erythrocytes by substantially reducing the hemolytic activity of the cyclic peptides compared with the linear peptides. Moreover, whereas the wt peptide was highly active toward gram(+) bacteria, its cyclic counterpart is active toward both gram(+) and gram(-) bacteria. These findings are correlated with an impaired ability of the cyclic analogues to bind and permeate zwitterionic phospholipid membranes compared with their linear counterparts and an increase in the binding and permeating activity of the cyclic wt peptide toward negatively charged membranes. Furthermore, cyclization abolished the oligomerization of the linear wt peptide in solution and in SDS, suggesting an additional factor that may account for the difference in the spectrum of antibacterial activity between the linear and the cyclic wt peptides. Interestingly, attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy revealed that, despite cyclization and incorporation of 33% D-amino acids along the peptide backbone, the membrane environment can impose a predominantly helical structure on the peptides, which is required for their bilogical function. Overall, our results indicate that linearity is not a prerequisite for lytic activity of amphipathic alpha-helical peptides but rather affects the selectivity between gram(+) and gram(-) bacteria and between mammalian cells and bacteria. In addition, the combination of incorporating of D-amino acids into lytic peptides and their cyclization open the way for developing a new group of antimicrobial peptides with improved properties for treating infectious diseases.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0006-2960
pubmed:author
pubmed:issnType
Print
pubmed:day
23
pubmed:volume
39
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
6103-14
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:10821683-Anti-Bacterial Agents, pubmed-meshheading:10821683-Electrophoresis, Polyacrylamide Gel, pubmed-meshheading:10821683-Growth Inhibitors, pubmed-meshheading:10821683-Hemolysis, pubmed-meshheading:10821683-Humans, pubmed-meshheading:10821683-Liposomes, pubmed-meshheading:10821683-Microbial Sensitivity Tests, pubmed-meshheading:10821683-Peptides, Cyclic, pubmed-meshheading:10821683-Permeability, pubmed-meshheading:10821683-Phosphatidylcholines, pubmed-meshheading:10821683-Phosphatidylethanolamines, pubmed-meshheading:10821683-Phosphatidylglycerols, pubmed-meshheading:10821683-Protein Binding, pubmed-meshheading:10821683-Protein Structure, Secondary, pubmed-meshheading:10821683-Solutions, pubmed-meshheading:10821683-Spectrometry, Fluorescence, pubmed-meshheading:10821683-Spectroscopy, Fourier Transform Infrared, pubmed-meshheading:10821683-Stereoisomerism, pubmed-meshheading:10821683-Structure-Activity Relationship, pubmed-meshheading:10821683-Tryptophan
pubmed:year
2000
pubmed:articleTitle
Cyclization of a cytolytic amphipathic alpha-helical peptide and its diastereomer: effect on structure, interaction with model membranes, and biological function.
pubmed:affiliation
Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, 76100 Israel.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't