Targeting C-reactive protein for the treatment of cardiovascular disease

By M. Pepys, Gideon M. Hirschfield, G. Tennent, J. Gallimore, M. Kahan, V. Bellotti, P. Hawkins, R. Myers, M. Smith, A. Polara and 11 more. Nature, 2006

711 citations recorded by the source corpus.

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.

Subfields: Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/7b4221e732fd92efd0009086293b35a82f54043c

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In Epidemiology

1. Nicola R. Sproston
2. J. Ashworth

In Molecular Biology

1. J. Forbes
2. Parisa Rashidi
3. M. Cooper
4. Patrick James Tighe
5. Azra Bihorac

Citations in the corpus

• Mechanisms of diabetic complications. (2013, background): “CVD accounts for more than half of the mortality seen in the diabetic population (228, 319), and diabetes equates to an approximately threefold increased risk of myocardial infarction compared with the general population (155).”
• Role of C-Reactive Protein at Sites of Inflammation and Infection (2018, background): “Thus, in addition to therapeutic strategies to inhibit CRP activity (51), more targeted therapies have been proposed for the treatment of CRP-mediated pathologies, including inhibiting mCRP activity (52) or preventing the dissociation of nCRP into mCRP (53).”
• C-reactive protein and the prediction of cardiovascular events among those at intermediate risk: moving an inflammatory hypothesis toward consensus. (2007, neutral): “One such agent has been described and, at least in animal models, has shown promise (98).”
• Artificial Intelligence and Surgical Decision-Making (2019, background): “34,43,56 Parametric regression equations also fail to represent the complex, nonlinear associations among input variables, further limiting the accuracy of traditional multivariable regression models.”