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PMID: 15282370 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: prevention of reperfusion injury.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 101 ·No. 32 ·2004-08-10 ·Pages 11791-6

Bertini R, Allegretti M, Bizzarri C, Moriconi A, Locati M, Zampella G, Cervellera MN, Di Cioccio V, Cesta MC, Galliera E, Martinez FO, Di Bitondo R, Troiani G, Sabbatini V, D'Anniballe G, Anacardio R, Cutrin JC, Cavalieri B, Mainiero F, Strippoli R, Villa P, Di Girolamo M, Martin F, Gentile M, Santoni A, Corda D, Poli G, Mantovani A, Ghezzi P, Colotta F

Abstract

The chemokine CXC ligand 8 (CXCL8)/IL-8 and related agonists recruit and activate polymorphonuclear cells by binding the CXC chemokine receptor 1 (CXCR1) and CXCR2. Here we characterize the unique mode of action of a small-molecule inhibitor (Repertaxin) of CXCR1 and CXCR2. Structural and biochemical data are consistent with a noncompetitive allosteric mode of interaction between CXCR1 and Repertaxin, which, by locking CXCR1 in an inactive conformation, prevents signaling. Repertaxin is an effective inhibitor of polymorphonuclear cell recruitment in vivo and protects organs against reperfusion injury. Targeting the Repertaxin interaction site of CXCR1 represents a general strategy to modulate the activity of chemoattractant receptors.

MeSH Terms
Allosteric Regulation/physiology Animals Binding Sites Humans Inflammation/metabolism Liver Diseases/pathology Models, Molecular Protein Conformation/drug effects Rats Receptors, Interleukin-8A/antagonists & inhibitors Reperfusion Injury/drug therapy,prevention & control Signal Transduction/drug effects Structure-Activity Relationship Sulfonamides/antagonists & inhibitors,pharmacology,therapeutic use
Chemicals
Receptors, Interleukin-8A Sulfonamides reparixin
Authors & Affiliations
30 authors, click to expand affiliations / ORCID
Bertini Riccardo
Dompé, 67100 L'Aquila, Italy.
Allegretti Marcello
Bizzarri Cinzia
Moriconi Alessio
Locati Massimo
Zampella Giuseppe
Cervellera Maria N
Di Cioccio Vito
Cesta Maria C
Galliera Emanuela
Martinez Fernando O
Di Bitondo Rosa
Troiani Giulia
Sabbatini Vilma
D'Anniballe Gaetano
Anacardio Roberto
Cutrin Juan C
Cavalieri Barbara
Mainiero Fabrizio
Strippoli Raffaele
Villa Pia
Di Girolamo Maria
Martin Franck
Gentile Marco
Santoni Angela
Corda Daniela
Poli Giuseppe
Mantovani Alberto
Ghezzi Pietro
Colotta Francesco
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0402090101
Published
2004-08-10
Epub
2004-00-28
Pages
11791-6
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC511013
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.0402090101 PMC Full Text View journal details
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