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

Riccardo Bertini; Marcello Allegretti; Cinzia Bizzarri; Alessio Moriconi; M. 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; M di Girolamo; FC Martin; Marco Gentile; Angela Santoni; Daniela Corda; Giuseppe Poli; A Mantovani; Pietro Ghezzi; Francesco Colotta

doi:10.1073/pnas.0402090101

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

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Peer reviewed

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

Riccardo Bertini, Marcello Allegretti, Cinzia Bizzarri, Alessio Moriconi, M. Locati, Giuseppe Zampella, Maria N Cervellera, Vito Di Cioccio, Maria C Cesta, Emanuela Galliera, …

Proceedings of the National Academy of Sciences - PNAS, Vol.101(32), pp.11791-11796

10/08/2004

DOI: https://doi.org/10.1073/pnas.0402090101

PMCID: PMC511013

PMID: 15282370

Abstract

Biological Sciences

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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Title: Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: Prevention of reperfusion injury
Creators: Riccardo Bertini - Dompé, 67100 L'Aquila, Italy
Marcello Allegretti - Dompé, 67100 L'Aquila, Italy
Cinzia Bizzarri - Dompé, 67100 L'Aquila, Italy
Alessio Moriconi - Dompé, 67100 L'Aquila, Italy
M. Locati - Dompé, 67100 L'Aquila, Italy
Giuseppe Zampella - Dompé, 67100 L'Aquila, Italy
Maria N Cervellera - Dompé, 67100 L'Aquila, Italy
Vito Di Cioccio - Dompé, 67100 L'Aquila, Italy
Maria C Cesta - Dompé, 67100 L'Aquila, Italy
Emanuela Galliera - Dompé, 67100 L'Aquila, Italy
Fernando O Martinez
Rosa Di Bitondo - Dompé, 67100 L'Aquila, Italy
Giulia Troiani - Dompé, 67100 L'Aquila, Italy
Vilma Sabbatini - Dompé, 67100 L'Aquila, Italy
Gaetano D'Anniballe - Dompé, 67100 L'Aquila, Italy
Roberto Anacardio - Dompé, 67100 L'Aquila, Italy
Juan C Cutrin - Dompé, 67100 L'Aquila, Italy
Barbara Cavalieri - Dompé, 67100 L'Aquila, Italy
Fabrizio Mainiero - Dompé, 67100 L'Aquila, Italy
Raffaele Strippoli - Dompé, 67100 L'Aquila, Italy
Pia Villa - Dompé, 67100 L'Aquila, Italy
M di Girolamo - Dompé, 67100 L'Aquila, Italy
FC Martin - Dompé, 67100 L'Aquila, Italy
Marco Gentile - Dompé, 67100 L'Aquila, Italy
Angela Santoni - Dompé, 67100 L'Aquila, Italy
Daniela Corda - Dompé, 67100 L'Aquila, Italy
Giuseppe Poli - Dompé, 67100 L'Aquila, Italy
A Mantovani - Dompé, 67100 L'Aquila, Italy
Pietro Ghezzi - Dompé, 67100 L'Aquila, Italy
Francesco Colotta - Dompé, 67100 L'Aquila, Italy
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.101(32), pp.11791-11796
Publisher: National Academy of Sciences
Date published: 10/08/2004
Identifiers: 99596922302346
Academic Unit: School of Biosciences
Language: English
Resource Type: Journal article

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

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