title: Synthesis and characterization of a novel inhibitor of C-reactive protein-mediated proinflammatory effects.
abstract: BACKGROUND
  Numerous studies have shown that high C-reactive protein (CRP) levels predict cardiovascular disease and augur a poor prognosis in patients with acute coronary syndromes. Much in vitro and in vivo data support of a role for CRP in atherogenesis. There is an urgent need to develop inhibitors that specifically block the biological effects of CRP in vivo. The one-bead-one-compound (OBOC) combinatorial library method has been used to discover ligands against several biological targets. In this study, we use a novel fluorescence-based screening method to screen an OBOC combinatorial library for the discovery of peptides against human CRP.
  
  
  METHODS
  Human CRP was labeled with fluorescein isothiocyanate (FITC) and human serum albumin (HuSA) was labeled with phycoerythrin (PE) and used for screening. The OBOC library LWH-01 was synthesized on TentaGel resin beads using a standard solid-phase "split/mix" approach.
  
  
  RESULTS
  By subtraction screening, eight peptides that bind specifically to CRP and not to HuSA were identified. In human aortic endothelial cells (HAECs) incubated with CRP, inhibitors CRPi-2, CRPi-3, and CRPi-6 significantly inhibited CRP-induced superoxide, cytokine release, and nuclear factor-κB (NFκB) activity. Molecular docking studies demonstrate that CRPi-2 interacts with the two Ca(2+) ions in the single subunit of CRP. The binding of CRPi-2 is reminiscent of choline binding.
  
  
  CONCLUSIONS
  Future studies will examine the utility of this inhibitor in animal models and clinical trials.
authors: Department of Pediatric Cancer Research, MD Anderson Cancer Center, Houston, TX 77030, USA. pkumaresan@mdanderson.org
authors: Pappanaicken R
authors: PR
authors: Kumaresan
authors: Sridevi
authors: S
authors: Devaraj
authors: Wenzhe
authors: W
authors: Huang
authors: Edmond Y
authors: EY
authors: Lau
authors: Ruiwu
authors: R
authors: Liu
authors: Kit S
authors: KS
authors: Lam
authors: Ishwarlal
authors: I
authors: Jialal
mesh_terms: D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001011:Aorta / Q000166:cytology / Q000187:drug effects; D002097:C-Reactive Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002478:Cells, Cultured; D020650:Combinatorial Chemistry Techniques / Q000379:methods; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D062105:Molecular Docking Simulation; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D019151:Peptide Library
chemical_list: D000893:Anti-Inflammatory Agents; D018836:Inflammation Mediators; D010446:Peptide Fragments; D019151:Peptide Library; D002097:C-Reactive Protein