Linked Life Data

9813253

Source:http://linkedlifedata.com/resource/pubmed/id/9813253

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
1998-11-30
pubmed:abstractText
Novel peptide 33mers have been designed by incorporating beta-conformation stabilizing residues from the beta-sheet domains of alpha-chemokines and functionally important residues from the beta-sheet domain of human neutrophil bactericidal protein (B/PI). B/PI is known for its ability to kill bacteria and to neutralize the action of bacterial endotoxin (lipopolysaccharide, LPS) which can induce septic shock leading to eventual death. Here, the goal was to make short linear peptides which demonstrate good beta-sheet folding and maintain bioactivity as in native B/PI. A library of 24 peptide 33mers (betapep-1 to betapep-24) were synthesized with various amino acid substitutions. CD and NMR data acquired in aqueous solution indicate that betapep peptides form beta-sheet structure to varying degrees and self-associate as dimers and tetramers like the alpha-chemokines. Bactericidal activity toward Gram-negative Pseudomonas aeruginosa was tested, and betapep-19 was found to be only about 5-fold less potent (62% kill at 1.2 x 10(-7) M) than native B/PI (80% kill at 2.9 x 10(-8) M). At LPS neutralization, betapep-2 and -23 were found to be most active (66-78% effective at 1.2 x 10(-6) M), being only about 50-100-fold less active than B/PI (50% at 1.5 x 10(-8) M). In terms of structure-activity relations, beta-sheet structural stability correlates with the capacity to neutralize LPS, but not with bactericidal activity. Although a net positive charge is necessary for activity, it is not sufficient for optimal activity. Hydrophobic residues tend to influence activities indirectly by affecting structural stability. Furthermore, results show that sequentially and spatially related residues from the beta-sheet domain of native B/PI can be designed into short linear peptides which show good beta-sheet folding and retain much of the native activity. This research contributes to the development of solutions to the problem of multiple drug-resistant, opportunistic microorganisms like P. aeruginosa and of agents effective at neutralizing bacterial endotoxin.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0006-3002
pubmed:author
pubmed:issnType
Print
pubmed:day
16
pubmed:volume
1425
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
81-92
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:9813253-Amino Acid Sequence, pubmed-meshheading:9813253-Animals, pubmed-meshheading:9813253-Anti-Bacterial Agents, pubmed-meshheading:9813253-Antimicrobial Cationic Peptides, pubmed-meshheading:9813253-Blood Bactericidal Activity, pubmed-meshheading:9813253-Blood Proteins, pubmed-meshheading:9813253-Circular Dichroism, pubmed-meshheading:9813253-Drug Design, pubmed-meshheading:9813253-Electrochemistry, pubmed-meshheading:9813253-Humans, pubmed-meshheading:9813253-Lipopolysaccharides, pubmed-meshheading:9813253-Magnetic Resonance Spectroscopy, pubmed-meshheading:9813253-Membrane Proteins, pubmed-meshheading:9813253-Molecular Sequence Data, pubmed-meshheading:9813253-Neutralization Tests, pubmed-meshheading:9813253-Peptides, pubmed-meshheading:9813253-Protein Structure, Secondary, pubmed-meshheading:9813253-Pseudomonas aeruginosa, pubmed-meshheading:9813253-Structure-Activity Relationship
pubmed:year
1998
pubmed:articleTitle
Designed beta-sheet-forming peptide 33mers with potent human bactericidal/permeability increasing protein-like bactericidal and endotoxin neutralizing activities.
pubmed:affiliation
Department of Biochemistry, Biomedical Engineering Center, University of Minnesota Health Science Center, Minneapolis 55455, USA. mayox001@maroon.tc.umn.edu
pubmed:publicationType
Journal Article, In Vitro, Research Support, Non-U.S. Gov't