Discovery & Green Chemical Synthesis of Anti-Cancer Drugs

发现

• 批准号: RGPIN-2014-04818
• 负责人: Yadav, Vikramaditya
• 金额: $ 1.53万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=611263
• 关键词: Discovery; Green; Chemical; Synthesis; Anti

It costs well in excess of a billion dollars and takes over a decade to discover and develop a new drug, and once a drug is approved, manufacturing it is not cheap either. The most efficient processes generate anywhere between 25 to 100 kg of waste for every kg of product. The rising cost of drug discovery and manufacturing has ominous portents for Canada’s publicly-funded healthcare system, especially cancer care. Cancer afflicts nearly 40% of Canadians and costs the nation as much as $22.5 billion each year, and unless new technologies that accelerate discovery and eliminate inefficiencies in the manufacturing train are developed, the economic burden of much-needed anti-cancer therapeutics could soon become insupportable for our nation. Fortunately, three recent developments in the life sciences and biochemical engineering offer a way out of the current crisis. At the outset, a sizable number of the over 100,000-strong family of terpenoid natural products have been characterised as being anti-cancerous and the biosynthetic reactions involved in their assembly are now known. Secondly, the cost of oligonucleotide synthesis is declining with each passing day, and, thirdly, we can genetically engineer microorganisms such as E. coli to undertake any enzymatic reaction with unprecedented ease and precision. Consequently, we propose re-engineering the metabolism of the simple bacterium E. coli to elicit the expression of combinations, permutations and mutations of known terpenoid biosynthetic reactions to synthesize novel anti-cancer therapeutics. Specifically, we propose (1) generating a library of terpenoids for screening drug leads, (2) developing a more efficient and economical microbial-aided route for manufacturing the blockbuster anti-cancer drug paclitaxel, (3) rationally designing and synthesising of novel tubulin-binding anti-cancer drugs, and (4) synthesising a chemical library using a novel, chemical genomic approach. Not only does the research proposed herein promise to re-populate the drying pipeline of anti-cancer drug candidates with molecules that have a high likelihood of clinical approval, but microbial-aided synthesis of pharmaceuticals is the ultimate demonstration of green and continuous chemical manufacturing. Students that will be trained in the research program proposed herein will lead the next generation of drug discovery and green chemistry in industry, academia and government.

发现和开发一种新药的成本远远超过10亿美元，需要10年以上的时间，而且一旦一种药物获得批准，生产它也不便宜。最有效的生产过程每生产一公斤产品会产生25到100公斤的废物。药物研发和制造成本的上升对加拿大公共资助的医疗保健系统，尤其是癌症治疗来说是不祥的预兆。癌症折磨着近40%的加拿大人，每年给国家造成的损失高达225亿美元。除非新技术能够加速发现和消除生产过程中的低效率，否则我们国家急需的抗癌治疗的经济负担可能很快就会变得无法承受。幸运的是，最近生命科学和生物化学工程的三个发展为摆脱当前的危机提供了一条出路。一开始，在超过10万种的萜类天然产物家族中，有相当数量的萜类天然产物被定性为具有抗癌作用，并且它们的组装所涉及的生物合成反应现在已经为人所知。其次，寡核苷酸合成的成本正在日益下降，第三，我们可以通过基因工程改造大肠杆菌等微生物，使其以前所未有的容易和精确进行任何酶的反应。因此，我们建议重新设计简单大肠杆菌的代谢，以引发已知萜类生物合成反应的组合，排列和突变的表达，以合成新的抗癌药物。具体来说，我们建议(1)建立一个萜类化合物文库，用于筛选药物先导物；(2)开发一种更高效、更经济的微生物辅助途径，用于生产畅销的抗癌药物紫杉醇；(3)合理设计和合成新的微管蛋白结合抗癌药物；(4)使用一种新的化学基因组方法合成化学文库。本文提出的研究不仅有望用极有可能获得临床批准的分子重新填充抗癌候选药物的干燥管道，而且微生物辅助药物合成是绿色和连续化学制造的最终演示。在本文提出的研究计划中接受培训的学生将在工业、学术界和政府中引领下一代药物发现和绿色化学。