1. 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
2. Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK
3. Endothelial Cell and Molecular Cardiology Group, Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, UK
4. Department of Primary Care and Population Sciences, Royal Free and University College Medical School, University College London, London NW3 2PF, UK
5. School of Biological Science, University of Southampton, Southampton SO16 7PX, UK
6. †Present addresses: Addenbrookes Hospital, Cambridge CB2 2QQ, UK (G.M.H.); Dip di Biochimica, Universitá di Pavia, Pavia 27100, Italy (V.B.); Department of Pharmaceutical Chemistry, University of Reading, Reading RG6 6AH, UK (A.J.A.C.); School of Biological Sciences, University of Wollongong, New South Wales 2522, Australia (J.A.A.); Department of Biochemistry, University of Sussex, Falmer BN1 9QG, UK (D.T.)

Correspondence to: Mark B. Pepys¹ Correspondence and requests for materials should be addressed to M.B.P. (Email: m.pepys@medsch.ucl.ac.uk).

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 complement¹, increases myocardial and cerebral infarct size in rats subjected to coronary or cerebral artery ligation, respectively^{2, 3}. Rat CRP does not activate rat complement, whereas human CRP activates both rat and human complement⁴. Administration of human CRP to rats is thus an excellent model for the actions of endogenous human CRP^{2, 3}. 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.

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