title: Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2 non-competitive allosteric inhibitor.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 [(35) S]-GTPγS binding approaches. The therapeutic potential of DF 2156A was evaluated in acute (liver ischaemia and reperfusion) and chronic (sponge-induced angiogenesis) experimental models of inflammation.
  
  
  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, TNF-α 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.
  
  
  CONCLUSIONS
  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.
authors: Dompé s.p.a., L'Aquila, Italy.
authors: R
authors: R
authors: Bertini
authors: L S
authors: LS
authors: Barcelos
authors: A R
authors: AR
authors: Beccari
authors: B
authors: B
authors: Cavalieri
authors: A
authors: A
authors: Moriconi
authors: C
authors: C
authors: Bizzarri
authors: P
authors: P
authors: Di Benedetto
authors: C
authors: C
authors: Di Giacinto
authors: I
authors: I
authors: Gloaguen
authors: E
authors: E
authors: Galliera
authors: M M
authors: MM
authors: Corsi
authors: R C
authors: RC
authors: Russo
authors: S P
authors: SP
authors: Andrade
authors: M C
authors: MC
authors: Cesta
authors: G
authors: G
authors: Nano
authors: A
authors: A
authors: Aramini
authors: J C
authors: JC
authors: Cutrin
authors: M
authors: M
authors: Locati
authors: M
authors: M
authors: Allegretti
authors: M M
authors: MM
authors: Teixeira
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004195:Disease Models, Animal; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D023062:Receptors, Interleukin-8A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D012867:Skin / Q000098:blood supply; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C511776:2'-((4'-trifluoromethanesulfonyloxy)phenyl)-N-methanesulfonylpropionamide; D000893:Anti-Inflammatory Agents; D016209:Interleukin-8; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D013449:Sulfonamides