Regulation of ADAMTS-5 activity by keratan sulphate-binding exosites

关节炎和肌肉骨骼疾病是澳大利亚残疾的主要原因。关节炎的负担不仅由患者，他们的家人和照顾者，而且劳动力市场和国民经济感到。迫切需要确定新的目标，设计廉价的关节炎疗法。TNF拮抗剂已被证明在治疗类风湿性关节炎（RA）中有效，但它们昂贵，通过注射给药，并且通常仅在澳大利亚用于对DMARD反应较差的患者。其长期疗效和安全性尚未确定。骨关节炎（OA）没有治疗方法，这种疾病随着年龄的增长而发生得更频繁，其特征是软骨和聚集蛋白聚糖的破坏。预防聚集蛋白聚糖分解的新药是OA迫切需要的，它们也将是治疗RA的DMARD的有价值的辅助疗法。我们已经发现主要的聚集蛋白聚糖降解酶是ADAMTS-5。因此，ADAMTS-5是关节炎治疗的潜在靶点。不幸的是，靶向ADAMTS-5的活性位点的药物预计会失败，因为ADAMTS-5的广泛组织分布，ADAMTS酶和基质金属蛋白酶（MMP）的活性位点之间的高水平同源性，以及MMP活性位点抑制剂在临床试验中的臭名昭著的失败。本项目的目的是确定ADAMTS-5的辅助结构域是否是活性位点的可行替代靶点。我们有证据表明，硫酸角质素，这是共价连接到聚集蛋白聚糖核心蛋白，可以调节聚集蛋白聚糖切割ADAMTS酶。我们的目标是确定开发阻断硫酸角质素结合的拮抗剂或阻断酶与其底物结合的硫酸角质素类似物的机会。这些数据将为制药行业提供通过ADAMTS-5调节聚集蛋白聚糖分解的新方向。

Arthritis and musculoskeletal conditions are the predominant cause of disability in Australia. The burden of arthritis is felt not only by patients, their families and carers, but also the labour market and the national economy. There is a pressing need to identify new targets for design of inexpensive arthritis therapies. The TNF antagonists have proved effective in managing rheumatoid arthritis (RA), but they are expensive, administered by injection, and in general, only prescribed in Australia for patients who respond poorly to DMARDs. Their long-term efficacy and safety is not yet determined. There are no treatments for osteoarthritis (OA), the disease that occurs more frequently with age and is characterised by destruction of cartilage and aggrecan. New drugs that protect against aggrecan breakdown are urgently needed for OA and they would also be valuable adjunct therapies to the DMARDs for treatment of RA. We have discovered that the major aggrecan-degrading enzyme is ADAMTS-5. ADAMTS-5 is, therefore, a potential target for arthritis therapies. Unfortunately, drugs targeting the active site of ADAMTS-5 are predicted to fail, given the wide tissue distribution of ADAMTS-5, the high level of homology between the active site of ADAMTS enzymes and matrix metalloproteinases (MMPs), and the notorious failure of MMP active site inhibitors in clinical trials. The aim of this project is to determine whether ancillary domains of ADAMTS-5 are a viable alternative target to the active site. We have evidence to suggest that keratan sulphate, which is covalently attached to the aggrecan core protein, can modulate aggrecan cleavage by ADAMTS enzymes. We aim to identify opportunities for developing antagonists that block keratan sulphate binding, or keratan sulphate analogues that block enzyme binding to its substrate. The data will inform the pharmaceutical industry on new directions for modulating aggrecanolysis by ADAMTS-5.