Development of a protein tyrosine kinase inhibitor for modification of GAG chains and prevention of atherosclerosis

澳大利亚的主要健康问题是肥胖和糖尿病引起的血管和心血管疾病。虽然基于生活方式改变的预防策略是可取的，但使用最新药物治疗心血管风险因素已被证明可以产生显着的益处。然而，尽管有药物治疗，仍有一大群患者患有心血管疾病。需要新的治疗方法，这些方法很可能直接针对血管。我们已经确定了一个生化机制，代表了血管壁定向治疗的主要目标，我们的目标是开发一种药物，以防止动脉粥样硬化，利用这一途径的治疗潜力。最近受到越来越多关注的一组大分子是蛋白聚糖，其是被带负电荷的基团大量包被的结合蛋白-糖分子。脂质在血管壁中的结合和滞留是动脉粥样硬化的主要原因。具体来说，蛋白聚糖上糖链（GAG）的长度决定了脂质的结合。我们已经发现了一类新的抑制剂，其直接靶向血管壁中的蛋白聚糖合成，并大大减少蛋白聚糖和脂质之间的相互作用。我们希望证明我们的化合物在动物模型中的功效，目的是显著降低动脉粥样硬化的发展速度和程度。这将为该化合物进入人体安全性试验奠定基础，并随后开发一种预防动脉粥样硬化的药物，从而减少心血管疾病。

The major health issue in Australia is vascular and cardiovascular disease resulting from obesity and diabetes. Whilst prevention strategies based on lifestyle changes are preferable, treating cardiovascular risk factors with the latest drugs has been shown to produce significant benefits. There is however a large group of patients who still acquire cardiovascular disease in spite of drug therapy. New therapies are required and these will most likely target blood vessels directly. We have identified a biochemical mechanism that represents a prime target for vascular wall directed therapy and we aim to exploit the therapeutic potential of this pathway by developing a drug to prevent atherosclerosis. A group of large molecules which have recently received increasing attention are the proteoglycans, combined protein-sugar molecules which are heavily coated with negatively charged groups. The binding and retention of lipids in the wall of the blood vessel is the main cause of atherosclerosis. Specifically, the length of the sugar (GAG) chains on the proteoglycans determines the binding of the lipids. We have discovered a new class of inhibitors which directly target proteoglycan synthesis in the vessel wall and greatly reduce the interaction between proteoglycans and lipids. We wish to demonstrate the efficacy of our compound in an animal model with the aim to produce a marked reduction in the rate and extent of development of atherosclerosis. This would lay the foundation for the compound to be taken into human safety trials and subsequently develop an agent for the prevention of atherosclerosis and a thus a reduction in cardiovascular disease.