Mapping the Effect of Excess Fatty Acids on Albumin-Drug Interactions by NMR

通过 NMR 绘制过量脂肪酸对白蛋白-药物相互作用的影响

• 批准号: 521727-2017
• 负责人: Melacini, Giuseppe
• 金额: $ 1.82万
• 依托单位: McMaster University
• 依托单位国家: 加拿大
• 项目类别: Engage Grants Program
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=640168
• 关键词: Mapping; Effect; Excess; Fatty; Acids

Therapure Biopharma Inc. (or Therapure in short) already developed a highly competitive product, referred tohere as "TBI-HSA", which is a therapeutic albumin designed for the cost-effective treatment of hypovolemiaand the control of oncotic pressure in surgical applications. Therapeutic albumin is also undergoing phase IIIclinical trials based on its potential use for treating dementia in Alzheimer's patients. The TBI-HSA biologicsis a viable alternative to traditional albumins obtained through Cohn's fractionation of pooled human plasmaand the prospect of future growth is excellent due to the rapidly aging population of Canada and the projectedincrease in demand for plasma biologics during surgeries. In order to fully exploit the full potential of thetechnology developed by Therapure for growth in these markets, it is essential to understand at the molecularlevel how the manufacturing process of TBI-HSA affects the active ingredient of this formulation, i.e. thealbumin protein. Here, we propose to determine through advanced Nuclear Magnetic Resonance (NMR)spectroscopy methods how a critical step of the TBI-HSA manufacturing process, the addition of stabilizers toenhance albumin stability, perturbs the interactions of albumin with common drugs, such as naproxen andwarfarin. Considering that alteration in these interactions affects the ability of albumin to function as abiotherapeutic, the molecular images provided by NMR will inform the future optimization of themanufacturing process implemented by Therapure. This type of optimization will provide Therapure a uniquecompetitive edge relative to its international competitors and thus will help Therapure significantly expand itsworldwide market. However, Therapure currently has no access to the specialized NMR expertise required togain this competitive edge. The Melacini group will provide the necessary expertise, as Dr. Melacinispecializes in the biophysical characterization of proteins by NMR. The application of these NMR imagingmethodologies to monitor how the TBI-HSA active ingredient changes during the manufacturing process willallow Therapure to further expand its share in the plasma biologics market.

Therapure Biopharma Inc.（简称Therapure）已经开发出一种极具竞争力的产品，在这里被称为“TBI-HSA”，这是一种治疗性白蛋白，用于低血容量治疗和外科应用中肿瘤压力的控制。基于治疗性白蛋白治疗阿尔茨海默病患者痴呆症的潜在用途，它也正在进行iii期临床试验。TBI-HSA生物制剂是一种可行的替代传统白蛋白的方法，传统白蛋白是通过Cohn的人类血浆分离获得的，由于加拿大人口的快速老龄化和手术期间血浆生物制剂需求的预计增加，未来的发展前景是良好的。为了充分利用由Therapure开发的技术在这些市场的增长潜力，有必要在分子水平上了解TBI-HSA的制造过程如何影响该配方的活性成分，即白蛋白。在这里，我们建议通过先进的核磁共振（NMR）波谱方法来确定TBI-HSA制造过程的关键步骤，即添加稳定剂以增强白蛋白稳定性，如何干扰白蛋白与常用药物（如萘普生和华法林）的相互作用。考虑到这些相互作用的改变会影响白蛋白作为无治疗药物的功能，核磁共振提供的分子图像将为Therapure实施的制造过程的未来优化提供信息。这种类型的优化将为Therapure提供相对于国际竞争对手的独特竞争优势，从而将帮助Therapure显著扩大其全球市场。然而，Therapure目前无法获得获得这种竞争优势所需的专业核磁共振专业知识。Melacini小组将提供必要的专业知识，因为Melacini博士擅长通过NMR对蛋白质进行生物物理表征。应用这些核磁共振成像方法来监测TBI-HSA活性成分在制造过程中的变化，将使Therapure进一步扩大其在血浆生物制剂市场的份额。