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

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

  • Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11791-6. doi: 10.1073/pnas.0402090101.
Riccardo Bertini 1,  Marcello Allegretti,  Cinzia Bizzarri,  Alessio Moriconi,  Massimo Locati,  Giuseppe Zampella,  Maria N Cervellera,  Vito Di Cioccio,  Maria C Cesta,  Emanuela Galliera,  Fernando O Martinez,  Rosa Di Bitondo,  Giulia Troiani,  Vilma Sabbatini,  Gaetano D'Anniballe,  Roberto Anacardio,  Juan C Cutrin,  Barbara Cavalieri,  Fabrizio Mainiero,  Raffaele Strippoli,  Pia Villa,  Maria Di Girolamo,  Franck Martin,  Marco Gentile,  Angela Santoni,  Daniela Corda,  Giuseppe Poli,  Alberto Mantovani,  Pietro Ghezzi,  Francesco Colotta
Affiliations

Affiliation

  • 1 Dompé, 67100 L'Aquila, Italy.
PMID: 15282370 DOI: 10.1073/pnas.0402090101
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.

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