title: Targeting C-reactive protein for the treatment of cardiovascular disease.
abstract: Complement-mediated inflammation exacerbates the tissue injury of ischaemic necrosis in heart attacks and strokes, the most common causes of death in developed countries. Large infarct size increases immediate morbidity and mortality and, in survivors of the acute event, larger non-functional scars adversely affect long-term prognosis. There is thus an important unmet medical need for new cardioprotective and neuroprotective treatments. We have previously shown that human C-reactive protein (CRP), the classical acute-phase protein that binds to ligands exposed in damaged tissue and then activates complement, increases myocardial and cerebral infarct size in rats subjected to coronary or cerebral artery ligation, respectively. Rat CRP does not activate rat complement, whereas human CRP activates both rat and human complement. Administration of human CRP to rats is thus an excellent model for the actions of endogenous human CRP. Here we report the design, synthesis and efficacy of 1,6-bis(phosphocholine)-hexane as a specific small-molecule inhibitor of CRP. Five molecules of this palindromic compound are bound by two pentameric CRP molecules, crosslinking and occluding the ligand-binding B-face of CRP and blocking its functions. Administration of 1,6-bis(phosphocholine)-hexane to rats undergoing acute myocardial infarction abrogated the increase in infarct size and cardiac dysfunction produced by injection of human CRP. Therapeutic inhibition of CRP is thus a promising new approach to cardioprotection in acute myocardial infarction, and may also provide neuroprotection in stroke. Potential wider applications include other inflammatory, infective and tissue-damaging conditions characterized by increased CRP production, in which binding of CRP to exposed ligands in damaged cells may lead to complement-mediated exacerbation of tissue injury.
authors.affiliation: Centre for Amyloidosis and Acute Phase Proteins, Department of Medicine, Royal Free and University College Medical School, University College London, Rowland Hill Street, London NW3 2PF, UK. m.pepys@medsch.ucl.ac.uk
authors.forename: Mark B
authors.initials: MB
authors.lastname: Pepys
authors.forename: Gideon M
authors.initials: GM
authors.lastname: Hirschfield
authors.forename: Glenys A
authors.initials: GA
authors.lastname: Tennent
authors.forename: J Ruth
authors.initials: JR
authors.lastname: Gallimore
authors.forename: Melvyn C
authors.initials: MC
authors.lastname: Kahan
authors.forename: Vittorio
authors.initials: V
authors.lastname: Bellotti
authors.forename: Philip N
authors.initials: PN
authors.lastname: Hawkins
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Myers
authors.forename: Martin D
authors.initials: MD
authors.lastname: Smith
authors.forename: Alessandra
authors.initials: A
authors.lastname: Polara
authors.forename: Alexander J A
authors.initials: AJ
authors.lastname: Cobb
authors.forename: Steven V
authors.initials: SV
authors.lastname: Ley
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Aquilina
authors.forename: Carol V
authors.initials: CV
authors.lastname: Robinson
authors.forename: Isam
authors.initials: I
authors.lastname: Sharif
authors.forename: Gillian A
authors.initials: GA
authors.lastname: Gray
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Sabin
authors.forename: Michelle C
authors.initials: MC
authors.lastname: Jenvey
authors.forename: Simon E
authors.initials: SE
authors.lastname: Kolstoe
authors.forename: Darren
authors.initials: D
authors.lastname: Thompson
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Wood
mesh_terms: D000818:Animals; D002097:C-Reactive Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D003165:Complement System Proteins / Q000276:immunology; D015195:Drug Design; D006586:Hexanes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D010767:Phosphorylcholine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar
chemical_list: C510236:1,6-bis(phosphocholine)-hexane; D006586:Hexanes; D010767:Phosphorylcholine; D003165:Complement System Proteins; D002097:C-Reactive Protein