There is epidemiological, clinical and experimental evidence that C-reactive protein (CRP), the classical acute phase protein, may contribute to atherogenesis, atherothrombosis and the tissue damage in myocardial infarction. The long-term objectives of this project are, first, to develop new drugs targeting CRP, in order to reduce tissue damage after atherothrombotic events, myocardial infarction and stroke, which are the most common cause of death in developed countries, and second, to establish whether CRP contributes to pathogenesis of atherosclerosis and/or atherothrombosis, opening the way to possible CRP-inhibitory prophylactic therapy. The applicant has lately designed novel low molecular weight chemical entities as ligands of CRP, which have been synthesized and shown to inhibit CRP binding in vitro and in experimental animals in vivo.
The specific aims now are further development of CRP inhibitors as drugs and their testing in vitro and in vivo on the pro-inflammatory, atherogenic and pro-atherothrombotic effects of CRP. Based on the properties and X-ray crystal structure of CRP, and the existing lead compounds, further new molecules will be designed and synthesized to achieve maximal affinity, inhibition of ligand binding and complement activation by CRP, and also depletion of circulating CRP in vivo. CRP has been reported to enhance tissue factor production and foam cell formation in vitro, which could be significant pro-atherothrombotic effects. These observations will be confirmed and extended with elucidation of the underlying mechanisms, including investigation of the action of CRP-inhibitory drugs. Apolipoprotein E knockout C57BL/6 mice spontaneously develop widespread severe atherosclerosis, including vulnerable plaque and possible atherothrombosis in the innominate artery. The applicant has introduced the human CRP transgene into these animals and will determine the effects of CRP on their phenotype and the modulation of these effects by CRP-inhibitory drugs. Finally, the applicant's observation that administration of human CRP increases infarct size in rats undergoing coronary or middle cerebral artery occlusion, will be extended to human CRP transgenic mice and protective effects of the CRP-inhibitory drugs will be sought, in both rats and mice, to provide critical proof of principle in support of clinical use of CRP inhibition as a novel therapeutic strategy.
| Casas, J P; Shah, T; Hingorani, A D et al. (2008) C-reactive protein and coronary heart disease: a critical review. J Intern Med 264:295-314 |
| Tennent, Glenys A; Hutchinson, Winston L; Kahan, Melvyn C et al. (2008) Transgenic human CRP is not pro-atherogenic, pro-atherothrombotic or pro-inflammatory in apoE-/- mice. Atherosclerosis 196:248-55 |
| Pepys, Mark B; Hawkins, Philip N; Kahan, Melvyn C et al. (2005) Proinflammatory effects of bacterial recombinant human C-reactive protein are caused by contamination with bacterial products, not by C-reactive protein itself. Circ Res 97:e97-103 |
