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: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=669112
• 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，需要十多年的时间，而且一旦药物获得批准，制造它的成本也不菲。最高效的流程每生产一公斤产品就会产生 25 至 100 公斤废物。药物发现和制造成本的不断上升对加拿大公共资助的医疗保健系统（尤其是癌症护理）来说是一个不祥的预兆。癌症困扰着近 40% 的加拿大人，每年给国家造成高达 225 亿美元的损失，除非开发出能够加速发现并消除生产链低效率的新技术，否则急需的抗癌治疗药物的经济负担很快就会变得我们国家无法承受。幸运的是，生命科学和生化工程领域的三项最新进展为摆脱当前危机提供了一条出路。最初，超过 100,000 种萜类天然产物家族中的相当一部分已被定性为具有抗癌作用，并且现在已知其组装过程中涉及的生物合成反应。其次，寡核苷酸合成的成本日益下降，第三，我们可以对大肠杆菌等微生物进行基因改造，以前所未有的轻松和精确度进行任何酶促反应。因此，我们建议重新设计简单细菌大肠杆菌的代谢，以引发已知萜类生物合成反应的组合、排列和突变的表达，从而合成新型抗癌疗法。具体来说，我们建议（1）生成用于筛选药物先导化合物的萜类化合物库，（2）开发一种更有效和更经济的微生物辅助路线来制造重磅抗癌药物紫杉醇，（3）合理设计和合成新型微管蛋白结合抗癌药物，以及（4）使用新型化学基因组方法合成化学库。本文提出的研究不仅有望用临床批准的可能性很高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证明。将接受本文提出的研究计划培训的学生将引领工业界、学术界和政府的下一代药物发现和绿色化学。