Switch to
| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
21
|
| pubmed:dateCreated |
1997-11-28
|
| pubmed:abstractText |
The migration, adhesion, and subsequent extravasation of leukocytes into inflamed tissues contribute to the pathogenesis of a variety of inflammatory diseases including asthma, rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. The integrin adhesion receptor alpha 4 beta 1 expressed on leukocytes binds to the extracellular matrix protein fibronectin and to the cytokine inducible vascular cell adhesion molecule-1 (VCAM-1) at inflamed sites. Binding of alpha 4 beta 1 to VCAM-1 initiates firm adhesion of the leukocyte to the vascular endothelium followed by extravasation into the tissue. Monoclonal antibodies generated against either alpha 4 beta 1 or VCAM-1 can moderate this inflammatory response in a variety of animal models. Recently peptides containing a consensus LDV sequence based on the connecting segment-1 (CS-1) of fibronectin and cyclic peptides containing an RCD motif have shown promise in modulating leukocyte migration and inflammation presumably by blocking the interaction of alpha 4 beta 1 with VCAM-1. Here we describe novel, highly potent, cyclic peptides that competitively inhibit alpha 4 beta 1 binding to VCAM-1 and fibronectin at sub nanomolar concentrations. The structure of a representative analog was determined via NMR spectroscopy and used to facilitate optimization of peptide leads. The peptides discussed here utilize similar functional groups as the binding epitope of VCAM-1, inhibit lymphocyte migration in vivo, and are highly selective for alpha 4 beta 1. Furthermore the structure--activity relationships described here have provided a template for the structure-based design of small molecule antagonists of alpha 4 beta 1-mediated cell adhesion processes.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Anti-Inflammatory Agents...,
http://linkedlifedata.com/resource/pubmed/chemical/Antibodies, Monoclonal,
http://linkedlifedata.com/resource/pubmed/chemical/Integrin alpha4beta1,
http://linkedlifedata.com/resource/pubmed/chemical/Integrins,
http://linkedlifedata.com/resource/pubmed/chemical/Peptides, Cyclic,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Lymphocyte Homing,
http://linkedlifedata.com/resource/pubmed/chemical/Vascular Cell Adhesion Molecule-1
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Oct
|
| pubmed:issn |
0022-2623
|
| pubmed:author |
pubmed-author:ArtisD RDR,
pubmed-author:BerisiniMM,
pubmed-author:BlackburnBB,
pubmed-author:BurnierJ PJP,
pubmed-author:ChaoJJ,
pubmed-author:ChuoNN,
pubmed-author:ClarkKK,
pubmed-author:FairbrotherW JWJ,
pubmed-author:FitzgeraldGG,
pubmed-author:FongSS,
pubmed-author:JacksonD YDY,
pubmed-author:JonesSS,
pubmed-author:MullinsSS,
pubmed-author:RawsonTT,
pubmed-author:RenzMM,
pubmed-author:StrubleMM,
pubmed-author:TingY CYC
|
| pubmed:issnType |
Print
|
| pubmed:day |
10
|
| pubmed:volume |
40
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
3359-68
|
| pubmed:dateRevised |
2006-11-15
|
| pubmed:meshHeading |
pubmed-meshheading:9341911-Animals,
pubmed-meshheading:9341911-Anti-Inflammatory Agents, Non-Steroidal,
pubmed-meshheading:9341911-Antibodies, Monoclonal,
pubmed-meshheading:9341911-Binding, Competitive,
pubmed-meshheading:9341911-Cell Adhesion,
pubmed-meshheading:9341911-Cell Movement,
pubmed-meshheading:9341911-Integrin alpha4beta1,
pubmed-meshheading:9341911-Integrins,
pubmed-meshheading:9341911-Lymphocytes,
pubmed-meshheading:9341911-Magnetic Resonance Spectroscopy,
pubmed-meshheading:9341911-Mass Spectrometry,
pubmed-meshheading:9341911-Mice,
pubmed-meshheading:9341911-Models, Molecular,
pubmed-meshheading:9341911-Molecular Structure,
pubmed-meshheading:9341911-Peptides, Cyclic,
pubmed-meshheading:9341911-Receptors, Lymphocyte Homing,
pubmed-meshheading:9341911-Structure-Activity Relationship,
pubmed-meshheading:9341911-Vascular Cell Adhesion Molecule-1
|
| pubmed:year |
1997
|
| pubmed:articleTitle |
Potent alpha 4 beta 1 peptide antagonists as potential anti-inflammatory agents.
|
| pubmed:affiliation |
Department of Bioorganic Chemistry, Genentech Inc., South San Francisco, California 94080, USA.
|
| pubmed:publicationType |
Journal Article
|