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Targeting C-reactive protein for the treatment of cardiovascular disease


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, respectively2,3. 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 CRP2,3. 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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Figure 1: Synthesis and structures of bis-phosphocholine compounds.
Figure 2: Nano electrospray mass spectra of CRP.
Figure 3: Structure of the complex of CRP with 1,6-bis(phosphocholine)-hexane.


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We thank R. Ganellin for a preliminary synthesis of bis(PC)-H by a different route, D. Moore, M. Neal, M. Singer and R. Stidwell for assistance with rat studies, and P. Vallance for advice. The study was funded by an MRC Programme Grant (M.B.P. and P.N.H.), a project grant from the US NIH National Heart, Lung and Blood Institute's Inflammation and Thrombosis Program (M.B.P.), The Wellcome Trust (S.P.W.) and Pentraxin Therapeutics Ltd. G.M.H. held an MRC Clinical Research Training Fellowship, M.D.S. holds a Royal Society University Research Fellowship and S.V.L. a Novartis Research Fellowship. Author Contributions The study was initiated, designed and directed by M.B.P., and the paper was written and the novel compounds were designed by M.B.P. and S.P.W. In vitro and in vivo experimental work was performed M.B.P., G.M.H., G.A.T., J.R.G., M.C.K and V.B. P.N.H. contributed to study design. Chemical syntheses were designed and performed by S.V.L., R.M.M., M.D.S., A.P. and A.J.A.C., and mass spectrometry was performed by J.A.A. and C.V.R. Myocardial infarction experiments were conducted by G.A.G. and I.S., C.A.S. performed statistical analyses, and S.P.W., M.C.J., S.E.K. and D.T. did the X-ray crystallography.

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Correspondence to Mark B. Pepys.

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M.B.P. is the inventor on a patent application identifying CRP as a therapeutic target, and M.B.P., S.V.L. and A.J.A.C. are the inventors on a patent application covering CRP inhibitor drugs. These applications are funded by UCL BioMedica PLC, the commercial exploitation arm of UCL, and Pentraxin Therapeutics Ltd, a University College London spinout company of which M.B.P. is a director. The other authors declare no competing financial interests.

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Pepys, M., Hirschfield, G., Tennent, G. et al. Targeting C-reactive protein for the treatment of cardiovascular disease. Nature 440, 1217–1221 (2006).

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