New marine natural product tools for drug discovery and chemical genetics

目前使用的药物有一半以上来自“天然产品”。海洋动物和微生物是药物发现中最大的未开发的新“天然产品”来源。我们拟议的研究旨在发现将为开发治疗新方法的候选药物提供先导化合物的海洋天然产品：a)糖尿病和肥胖症，b)SARS，c)器官移植排斥反应，d)囊性纤维化。糖尿病影响200万加拿大人，每年花费国家90亿美元。患有糖尿病或肥胖症的患者的预期寿命会缩短，而且容易患高血压、心血管疾病、癌症、中风、肾衰竭和失明。人胰腺α-淀粉酶(HPA)是治疗糖尿病和肥胖症的新药开发的一个很有前途的靶点。我们正在提议寻找新的HPA抑制剂。非典最早出现在中国身上，最终蔓延至全球，包括加拿大。在2002年爆发期间，有9000人感染SARS，其中774人死亡。目前还没有治疗SARS的小分子药物。我们建议寻找SARS蛋白酶的抑制剂3CLPro，它已被确定为开发抗SARS药物的有前途的靶点。钙调神经磷酸酶是一种蛋白磷酸酶，是免疫抑制药物环孢素和FK506的间接细胞靶点。尽管这些是给器官移植带来革命性变化的重要药物，但它们也有严重的副作用。尽管钙调神经磷酸酶抑制剂在临床上很重要，但目前还没有好的这种磷酸酶的活性部位抑制剂。我们建议寻找钙调神经磷酸酶的活性部位抑制剂，作为开发一类新的免疫抑制药物的先导。囊性纤维化是影响高加索人的最常见的致命性遗传病。大多数囊性纤维化患者的预期寿命只有34岁。CF是由CFTR基因的苯丙氨酸缺失(DeltaF508)突变引起的，导致CFTR基因产物的错误折叠和功能降低。我们建议寻找deltaF508-CFTR缺陷“校正器”，它们被认为是治疗CF的有效药物。

More than half of currently used drugs are derived from 'natural products'. Marine animals and microbes represent the greatest unexplored source of new 'natural products' for drug discovery. Our proposed research is designed to discover 'marine natural products' that will provide lead compounds for developing drug candidates for new approaches to treating: a) diabetes and obesity, b) SARS, c) rejection of organ transplants, and d) cystic fibrosis.  Diabetes affects 2 million Canadians and  costs the country 9 billion dollars annually. Patients suffering from diabetes or obesity experience shortened life expectancy and are susceptible to hypertension, cardiovascular disease, cancer, stroke, kidney failure, and blindness. Human pancreatic alpha amylase (HPA) is a promising target for the development of new drugs for treating diabetes and obesity. We are proposing to search for new inhibitors of  HPA. SARS first appeared in China and eventually spread worldwide, including to Canada. During the 2002 outbreak, 9000 individuals contracted SARS and there were 774 fatalities. There are no small molecule drugs to treat SARS. We are proposing to search for inhibitors of the SARS protease, 3CLpro, which has been identified as a promising target for developing anti-SARS drugs. Calcineurin, a protein phosphatase, is the indirect cellular target of the immunosuppressive drugs cyclosporine and FK506. Even though these are important drugs that have revolutionized organ transplantation, they have serious side effects. Despite the clinical importance of calcineurin inhibitors, there are no good active-site inhibitors of this phosphatase known. We are proposing to search for active-site inhibitors of calcineurin that would act as leads for development of a new class of immunosuppressive drugs. Cystic Fibrosis (CF) is the most common lethal genetic disease affecting Caucasians.  CF patients have an expected life span of only 34 years. CF is caused by a phenylalanine deletion (deltaF508) mutation in the CFTR gene leading to misfolding and decreased function of the CFTR gene product. We propose to search for deltaF508-CFTR defect 'correctors', which are hypothesized to be useful drugs for treating CF.