A CXCL8 receptor antagonist based on the structure of N-acetyl-proline- glycine-proline

Academic Article

Abstract

  • A role for the collagen-derived tripeptide, N-acetyl proline-glycine- proline (NAc-PGP), in neutrophil recruitment in chronic airway inflammatory diseases, including COPD and cystic fibrosis, has recently been delineated. Due to structural similarity to an important motif for interleukin-8 (CXCL8) binding to its receptor, NAc-PGP binds to CXCR1/2 receptors, leading to neutrophil activation and chemotaxis. In an effort to develop novel CXCL8 antagonists, we describe the synthesis of four chiral isomers of NAc-PGP (NAc-l-Pro-Gly-l-Pro (ll-NAc-PGP), NAc-l-Pro-Gly-d-Pro (lD-NAc-PGP), NAc-d-Pro-Gly-l-Pro (dl-NAc-PGP), and NAc-d-Pro-Gly-d-Pro (dd-NAc-PGP)), characterize them by circular dichroism and NMR spectroscopy, compare their structures to the equivalent region of CXCL8, and test them as potential antagonists of ll-NAc-PGP and CXCL8. We find that ll-NAc-PGP superimposes onto the CXCR1/2 contacting E 29S 30G 31P 32 region of CXCL8 (0.59A rmsd for heavy atoms). In contrast, dd-NAc-PGP has an opposing orientation of key functional groups as compared to the G 31P 32 region of CXCL8. As a consequence, dd-NAc-PGP binds CXCR1/2, as demonstrated by competition with radiolabeled CXCL8 binding in a radioreceptor assay, yet acts as a receptor antagonist as evidenced by inhibition of CXCL8 and ll-NAc-PGP mediated neutrophil chemotaxis. The ability of dd-NAc-PGP to prevent the activation of CXC receptors indicates that dd-NAc-PGP may serve as a lead compound for the development of CXCR1/2 inhibitors. In addition, this study further proves that using a different technical approach, namely preincubation of NAc-PGP instead of simultaneous addition of NAc-PGP with radiolabeled CXCL8, the direct binding of NAc-PGP to the CXCL8 receptor is evident. © 2011 Elsevier B.V. All rights reserved.
  • Digital Object Identifier (doi)

    Author List

  • Jackson PL; Noerager BD; Jablonsky MJ; Hardison MT; Cox BD; Patterson JC; Dhanapal B; Blalock JE; Muccio DD
  • Start Page

  • 435
  • End Page

  • 442
  • Volume

  • 668
  • Issue

  • 3