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.（或简称 Therapure）已经开发出一种极具竞争力的产品，此处称为“TBI-HSA”，这是一种治疗性白蛋白，设计用于经济有效地治疗低血容量和控制手术应用中的胶体渗透压。治疗性白蛋白也正在进行 III 期临床试验，因为它可能用于治疗阿尔茨海默氏症患者的痴呆症。 TBI-HSA 生物制剂是通过科恩分离混合人血浆获得的传统白蛋白的可行替代品，并且由于加拿大人口迅速老龄化以及预计手术期间对血浆生物制剂的需求增加，未来增长前景良好。为了充分发挥 Therapure 开发的技术在这些市场中的增长潜力，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) 波谱方法确定 TBI-HSA 制造过程的关键步骤（添加稳定剂以增强白蛋白稳定性）如何扰乱白蛋白与常见药物（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非生物治疗药物的能力，NMR 提供的分子图像将为 Therapure 实施的制造工艺的未来优化提供信息。这种类型的优化将为 Therapure 提供相对于其国际竞争对手的独特竞争优势，从而帮助 Therapure 显着扩大其全球市场。然而，Therapure 目前无法获得获得这一竞争优势所需的专业 NMR 专业知识。 Melacini 团队将提供必要的专业知识，因为 Melacini 博士专门研究通过 NMR 进行蛋白质的生物物理表征。应用这些 NMR 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。