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: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=588036
• 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，而且一旦药物被批准，制造它也不便宜。最有效的工艺每公斤产品会产生25至100公斤的废物。药物发现和制造成本的上升对加拿大公共资助的医疗保健系统，特别是癌症护理有不祥的预兆。癌症困扰着近40%的加拿大人，每年花费高达225亿美元，除非开发出加速发现和消除制造业效率低下的新技术，否则急需的抗癌疗法的经济负担可能很快就会变得无法承受。幸运的是，生命科学和生物化学工程领域的三项最新进展为摆脱当前的危机提供了一条出路。一开始，超过100，000个强大的萜类天然产物家族中的相当数量已被表征为抗癌，并且现在已知其组装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，我们可以通过基因工程改造微生物，如大肠杆菌。大肠杆菌进行任何酶反应前所未有的轻松和精确。因此，我们建议重新设计简单细菌E.大肠杆菌中诱导已知萜类生物合成反应的组合、排列和突变的表达，以合成新的抗癌治疗剂。具体来说，我们建议（1）产生一个萜类化合物库用于筛选药物线索，（2）开发一种更有效和经济的微生物辅助途径用于制造重磅炸弹抗癌药物紫杉醇，（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文库。本文提出的研究不仅有望用具有高临床批准可能性的分子重新填充抗癌药物候选物的干燥管道，而且药物的微生物辅助合成是绿色和连续化学制造的最终证明。将在本文提出的研究计划中接受培训的学生将在工业界，学术界和政府中领导下一代药物发现和绿色化学。