Preferred binding regions for highly selective and orthogonal multimodal protein separations

高选择性和正交多模式蛋白质分离的优选结合区域

• 批准号: 1704745
• 负责人: Steven Cramer
• 金额: $ 32.65万
• 依托单位: Rensselaer Polytechnic Institute
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1704745&HistoricalAwards=false
• 关键词: Preferred; binding; regions; highly; selective

The development of protein-based medicines is having an increasing impact on treatment of many diseases such as cancer, diabetes, and multiple sclerosis. Example protein-based therapeutics for these diseases include rituxan, insulin, and avonex, respectively, with many more in various stages of discovery and development. However, the costs of producing these drugs and the challenge of obtaining highly pure drugs with minimal side effects is a major challenge. Often, negative side effects are due to small amounts of impurities that are extremely similar to the desired medicine and thus very difficult to remove. This NSF funded project will develop new methods for efficiently removing these challenging drug impurities from a range of biopharmaceuticals, resulting in reduced production costs, safer medicines and more patient access.This experimental and computational project will focus on the development of multimodal ligands for chromatographic resins, which will be used to achieve highly selective separations of complex biological products. The new multimodal ligands will increase selectivity by targeting specific regions on protein surfaces, enabling the effective removal of bioproduct related impurities, a critical challenge in biomanufacturing. Experimental characterization techniques will validate molecular-level binding information. The computational work will predict key binding faces and relative binding affinities and will produce powerful predictive tools for bioprocess development. The development of multimodal systems with unique and targeted selectivities on specific protein surface regions will enable the development of highly effective orthogonal downstream processes guided by molecular level understanding and predictive tools. This will result in reduced costs and improved product quality and safety. Graduate and undergraduate students working on this project will be directly exposed to the state of the art in biophysics, chromatography and molecular simulations. More broadly, the concepts will be incorporated into both undergraduate coursework and on-line animated movies for the the Molecularium project, the flagship outreach and education effort of Rensselaer Polytechnic Institute's Nanotechnology Center.

基于蛋白质的药物的发展对许多疾病如癌症、糖尿病和多发性硬化症的治疗产生越来越大的影响。用于这些疾病的示例性基于蛋白质的治疗剂分别包括rituxan、胰岛素和avonex，还有更多处于不同的发现和开发阶段。 然而，生产这些药物的成本和获得具有最小副作用的高纯度药物的挑战是一个重大挑战。通常，负面的副作用是由于少量的杂质与所需的药物非常相似，因此很难去除。NSF资助的这个项目将开发新的方法，有效地从一系列生物制药中去除这些具有挑战性的药物杂质，从而降低生产成本，更安全的药物和更多的患者访问。这个实验和计算项目将专注于开发色谱树脂的多峰配体，用于实现复杂生物产品的高选择性分离。新的多峰配体将通过靶向蛋白质表面的特定区域来提高选择性，从而有效去除生物产品相关杂质，这是生物制造中的一个关键挑战。实验表征技术将验证分子水平的结合信息。 计算工作将预测关键的结合面和相对结合亲和力，并将产生强大的预测工具的生物过程的发展。在特定蛋白质表面区域上具有独特和靶向选择性的多模式系统的开发将能够开发由分子水平理解和预测工具指导的高效正交下游过程。这将降低成本，提高产品质量和安全性。从事该项目的研究生和本科生将直接接触到生物物理学、色谱和分子模拟方面的最新技术。 更广泛地说，这些概念将被纳入本科课程和在线动画电影的分子项目，旗舰推广和教育努力伦斯勒理工学院的纳米技术中心。

项目成果

Evaluation of guanidine-based multimodal anion exchangers for protein selectivity and orthogonality

基于胍的多模式阴离子交换剂的蛋白质选择性和正交性评估

• DOI: 10.1016/j.chroma.2021.462398
• 发表时间: 2021
• 期刊: Journal of Chromatography A
• 影响因子: 4.1
• 作者: Koley, Sushmita;Altern, Scott H.;Vats, Mayank;Han, Xuan;Jang, Dongyoun;Snyder, Mark A.;Belisle, Chris;Cramer, Steven M.
• 通讯作者: Cramer, Steven M.

Quantifying orthogonality and separability: A method for optimizing resin selection and design

量化正交性和可分离性：优化树脂选择和设计的方法

• DOI: 10.1016/j.chroma.2020.461429
• 发表时间: 2020
• 期刊: Journal of Chromatography A
• 影响因子: 4.1
• 作者: Bilodeau, Camille L.;Vecchiarello, Nicholas A.;Altern, Scott;Cramer, Steven M.
• 通讯作者: Cramer, Steven M.

Conformational Equilibria of Multimodal Chromatography Ligands in Water and Bound to Protein Surfaces

水中和蛋白质表面结合的多模式色谱配体的构象平衡

• DOI: 10.1021/acs.jpcb.9b01218
• 发表时间: 2019
• 期刊: The Journal of Physical Chemistry B
• 作者: Bilodeau, Camille L.;Lau, Edmond Y.;Cramer, Steven M.;Garde, Shekhar
• 通讯作者: Garde, Shekhar

Behavior of Water Near Multimodal Chromatography Ligands and Its Consequences for Modulating Protein–Ligand Interactions

水在多模式色谱配体附近的行为及其对调节蛋白质与配体相互作用的影响

• DOI: 10.1021/acs.jpcb.1c01549
• 发表时间: 2021
• 期刊: The Journal of Physical Chemistry B
• 作者: Bilodeau, Camille L.;Lau, Edmond Y.;Roush, David J.;Snyder, Mark A.;Cramer, Steven M.
• 通讯作者: Cramer, Steven M.

A thermodynamic evaluation of antibody-surface interactions in multimodal cation exchange chromatography

多模式阳离子交换色谱中抗体-表面相互作用的热力学评估

• DOI: 10.1016/j.chroma.2020.461479
• 发表时间: 2020
• 期刊: Journal of Chromatography A
• 影响因子: 4.1
• 作者: Gudhka, Ronak B.;Roush, David J.;Cramer, Steven M.
• 通讯作者: Cramer, Steven M.