Linked Life Data

10197961

Source:http://linkedlifedata.com/resource/pubmed/id/10197961

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
7
pubmed:dateCreated
1999-5-20
pubmed:abstractText
Experimental allergic encephalomyelitis (EAE) is induced in susceptible animals by immunodominant determinants of myelin basic protein (MBP), such as guinea pig sequence MBP72-85. Two linear and one cyclic analogues based on MBP72-85 have been synthesized and evaluated for EAE induction in Lewis rats. The linear peptide Gln1-Lys2-Ser3-Gln4-Arg5-Ser6-Gln7-+ ++Asp8-Glu9-Asn10-Pro11-Val12 (1) was found to induce EAE, while substitution of the Asp residue at position 8 with Ala resulted in an analogue (2) which suppressed the induction of EAE by its parent peptide. Nuclear magnetic resonance studies of analogue 1 in dimethyl sulfoxide (DMSO) using TOCSY/ROESY techniques revealed a head-to-tail intramolecular interaction (ROE connectivity between betaVal12-gammaGln1), indicating a pseudocyclic conformation for the immunogenic peptide 1. A conformational model was developed using NMR constraints and molecular dynamics. Based on this model, a novel amide-linked cyclic analogue has been designed and synthesized by connecting the side-chain amino and carboxyl groups of Lys and Glu at positions 2 and 9, respectively, of linear analogue 1. The cyclic analogue (3) had similar activity to the linear peptide 1, and the EAE effects induced by cyclic analogue 3 were completely suppressed by co-injection with the Ala81-substituted analogue 2 in Lewis rats. The similar potencies of analogues 1 and 3 support the proposed cyclic comformation suggested for analogue 1 from NMR studies and computer modeling and provides the basis for designing more potent molecules with improved properties such as increased resistance to degradation.15 The present findings suggest that a cyclic conformation for the MBP72-85 epitope positions the carboxyl group of Asp81 correctly and presumably other side groups of the peptide such as Arg78 in a manner which enables functional binding of the trimolecular complex MHC-peptide-T cell receptor resulting in EAE.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
8
pubmed:volume
42
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1170-7
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:10197961-Alanine, pubmed-meshheading:10197961-Animals, pubmed-meshheading:10197961-Chromatography, High Pressure Liquid, pubmed-meshheading:10197961-Drug Design, pubmed-meshheading:10197961-Encephalomyelitis, Autoimmune, Experimental, pubmed-meshheading:10197961-Epitopes, pubmed-meshheading:10197961-Gas Chromatography-Mass Spectrometry, pubmed-meshheading:10197961-Magnetic Resonance Spectroscopy, pubmed-meshheading:10197961-Models, Molecular, pubmed-meshheading:10197961-Myelin Basic Proteins, pubmed-meshheading:10197961-Peptide Fragments, pubmed-meshheading:10197961-Peptides, Cyclic, pubmed-meshheading:10197961-Protein Conformation, pubmed-meshheading:10197961-Rats, pubmed-meshheading:10197961-Rats, Inbred Lew, pubmed-meshheading:10197961-Structure-Activity Relationship
pubmed:year
1999
pubmed:articleTitle
Design and synthesis of a potent cyclic analogue of the myelin basic protein epitope MBP72-85: importance of the Ala81 carboxyl group and of a cyclic conformation for induction of experimental allergic encephalomyelitis.
pubmed:affiliation
Department of Chemistry, University of Patras, 26500 Patras, Greece.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't