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

doi:10.1073/pnas.0402090101

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

^*Dompé, 67100 L'Aquila, Italy; ^‡Centro per l'Innovazione Diagnostica e Terapeutica, Milan University, 20133 Milan, Italy; ^§Milano–Bicocca University, 20100 Milan, Italy; ^¶Turin University, 10043 Turin, Italy; ^∥La Sapienza, Università delgi Studi di Roma, 00161 Rome, Italy; ^**Mario Negri Institute, 20157 Milan, Italy; ^††Consiglio Nazionale delle Ricerche, 20133 Milan, Italy; and ^‡‡Mario Negri Sud, 66030 Chieti, Italy

Edited by Charles A. Dinarello, University of Colorado Health Sciences Center, Denver, CO, and approved June 23, 2004 (received for review March 25, 2004)

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.

Footnotes

↵ §§ To whom correspondence should be addressed at: Dompé, Via Campo di Pile, 67100 L'Aquila, Italy. E-mail: colotta{at}dompe.it.
↵ † R.B. and M.A. contributed equally to this work.
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.