Targeting C-reactive protein for the treatment of cardiovascular disease

Aiming for the heart C-reactive protein (CRP) is a clinical marker for inflammatory disease and infection, but it also binds to damaged cells and activates complement, a host defence and pro-inflammatory system of serum proteins. Complement-mediated inflammation exacerbates tissue injury in heart attacks, and human CRP increases damage in a rat model of acute myocardial infarction via a complement-dependent mechanism. These observations point to CRP as a possible target for drugs intended to protect the heart. Pepys et al . therefore designed a specific small-molecule CRP inhibitor. Five molecules of this palindromic compound are bound by two pentameric CRP molecules arranged face-to-face, as in the X-ray crystal structure of the complex on the cover. The inhibitor blocks the adverse effects of human CRP in rats with acute myocardial infarction, suggesting that early therapeutic inhibition of CRP might be beneficial for heart attack patients. A new drug inhibits the adverse effects of C-reactive protein, a blood protein that has been shown to exacerbate damage in the heart and brain after blockage of the blood supply. 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 1 , 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 complement 4 . 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 a