Noncompetitive Allosteric Inhibitors of the Inflammatory Chemokine Receptors CXCR1 and CXCR2: Prevention of Reperfusion Injury

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 biochemica...

Full description

Saved in:
Bibliographic Details
Published inProceedings of the National Academy of Sciences - PNAS Vol. 101; no. 32; pp. 11791 - 11796
Main Authors Bertini, Riccardo, 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, Dinarello, Charles A.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 10.08.2004
National Acad Sciences
Subjects
Allosteric Regulation - physiology
Animals
Binding Sites
Biological Sciences
Chemokines
Human migration
Humans
Inflammation - metabolism
Injuries
Ligands
Liver
Liver Diseases - pathology
Medical research
Models, Molecular
Molecular interactions
Neutrophils
Protein Conformation - drug effects
Rats
Receptors
Receptors, Interleukin-8A - antagonists & inhibitors
Reperfusion
Reperfusion injury
Reperfusion Injury - drug therapy
Reperfusion Injury - prevention & control
Signal Transduction - drug effects
Structure-Activity Relationship
Sulfonamides - antagonists & inhibitors
Sulfonamides - pharmacology
Sulfonamides - therapeutic use
Tissues
Vehicles
Online AccessGet full text

Cover

More Information
Summary: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.
Bibliography:ObjectType-Article-2
SourceType-Scholarly Journals-1
ObjectType-Feature-1
content type line 23
ObjectType-Article-1
ObjectType-Feature-2
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: CLP, cecal ligation puncture; COX, cyclooxygenase; GPCR, G protein-coupled receptors; RI, reperfusion injury; CXCL8, CXC ligand 8; CXCR1/2, CXC receptors 1 and 2; PMN, polymorphonuclear cell; fMLP, N-formyl-l-methionyl-l-leucyl-l-phenylalanine; TM, transmembrane; CCR, CC chemokine receptor.
To whom correspondence should be addressed at: Dompé, Via Campo di Pile, 67100 L'Aquila, Italy. E-mail: colotta@dompe.it.
R.B. and M.A. contributed equally to this work.
Edited by Charles A. Dinarello, University of Colorado Health Sciences Center, Denver, CO, and approved June 23, 2004
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0402090101