Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2 non-competitive allosteric inhibitor

被引：62

作者：

Bertini, R. ^{[1
,10
]}

Barcelos, L. S. ^{[2
,6
]}

Beccari, A. R. ^{[1
]}

Cavalieri, B. ^{[1
,3
]}

Moriconi, A. ^{[1
]}

Bizzarri, C. ^{[1
]}

Di Benedetto, P. ^{[1
]}

Di Giacinto, C. ^{[1
]}

Gloaguen, I. ^{[1
]}

Galliera, E. ^{[4
]}

Corsi, M. M. ^{[4
,5
]}

Russo, R. C. ^{[2
,6
]}

Andrade, S. P. ^{[2
]}

Cesta, M. C. ^{[1
]}

Nano, G. ^{[1
]}

Aramini, A. ^{[1
]}

Cutrin, J. C. ^{[3
,7
,9
]}

Locati, M. ^{[8
,11
]}

Allegretti, M. ^{[1
]}

Teixeira, M. M. ^{[6
]}

机构：

[1] Dompe Spa, I-67100 Laquila, Italy

[2] Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Fisiol & Biofis, Belo Horizonte, MG, Brazil

[3] Univ Turin, Dept Clin & Biol Sci, Turin, Italy

[4] Univ Milan, Dept Human Morphol & Biomed Sci Citta Studi, Milan, Italy

[5] Policlin San Donato IRCCS, San Donato Milanese, Italy

[6] Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Bioquim & Immunol, Belo Horizonte, MG, Brazil

[7] Univ Buenos Aires, Sch Med, Ctr Expt Pathol, RA-1053 Buenos Aires, DF, Argentina

[8] Univ Milan, Dept Translat Med, Milan, Italy

[9] Consejo Nacl Invest Cient & Tecn, RA-1033 Buenos Aires, DF, Argentina

[10] ALTA Srlu, Laquila, Italy

[11] Ist Clin Humanitas IRCCS, Milan, Italy

来源：

BRITISH JOURNAL OF PHARMACOLOGY | 2012年 / 165卷 / 02期

关键词：

chemokine receptors; CXCR1; CXCR2; non-competitive allosteric inhibitor; binding mode; leucocyte recruitment; experimental angiogenesis; ischaemia reperfusion injury; ENDOTHELIAL GROWTH-FACTOR; MONOCYTE CHEMOATTRACTANT PROTEIN-1; ISCHEMIA-REPERFUSION INJURY; DELAYED GRAFT FUNCTION; T-CELL RECRUITMENT; CXC CHEMOKINES; MONOCLONAL-ANTIBODY; HUMAN NEUTROPHILS; RAT-LIVER; ISCHEMIA/REPERFUSION;

D O I：

10.1111/j.1476-5381.2011.01566.x

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

BACKGROUND AND PURPOSE DF 2156A is a new dual inhibitor of IL-8 receptors CXCR1 and CXCR2 with an optimal pharmacokinetic profile. We characterized its binding mode, molecular mechanism of action and selectivity, and evaluated its therapeutic potential. EXPERIMENTAL APPROACH The binding mode, molecular mechanism of action and selectivity were investigated using chemotaxis of L1.2 transfectants and human leucocytes, in addition to radioligand and [S-35]-GTP gamma S binding approaches. The therapeutic potential of DE 2156A was evaluated in acute (liver ischaemia and reperfusion) and chronic (sponge-induced angiogenesis) experimental models of inflammation. KEY RESULTS A network of polar interactions stabilized by a direct ionic bond between DF 2156A and Lys(99) on CXCR1 and the non-conserved residue Asp(293) on CXCR2 are the key determinants of DF 2156A binding. DF 2156A acted as a non-competitive allosteric inhibitor blocking the signal transduction leading to chemotaxis without altering the binding affinity of natural ligands. DF 2156A effectively and selectively inhibited CXCR1/CXCR2-mediated chemotaxis of L1.2 transfectants and leucocytes. In a murine model of sponge-induced angiogenesis, DF 2156A reduced leucocyte influx, INF-alpha production and neovessel formation. In vitro, DF 2156A prevented proliferation, migration and capillary-like organization of HUVECs in response to human IL-8. In a rat model of liver ischaemia and reperfusion (I/R) injury, DF 2156A decreased PMN and monocyte-macrophage infiltration and associated hepatocellular injury. CONCLUSION AND IMPLICATIONS DF 2156A is a non-competitive allosteric inhibitor of both IL-8 receptors CXCR1 and CXCR2. It prevented experimental angiogenesis and hepatic I/R injury in vivo and, therefore, has therapeutic potential for acute and chronic inflammatory diseases.

引用

页码：436 / 454

页数：19

共 70 条

[1] Liver Ischemia/Reperfusion Injury: Processes in Inflammatory Networks-A Review [J].