Synthesis and characterization of a novel inhibitor of c-reactive protein-mediated proinflammatory effects

Pappanaicken R. Kumaresan, Sridevi Devaraj, Wenzhe Huang, Edmond Y Lau, Ruiwu Liu, Kit Lam, Ishwarlal Jialal

Research output: Contribution to journalArticle

6 Scopus citations

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 Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)177-184
Number of pages8
JournalMetabolic Syndrome and Related Disorders
Volume11
Issue number3
DOIs
StatePublished - Jun 1 2013

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Internal Medicine

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