RUI: Combinatorial Synthesis of Protein-Polymer Conjugates by Post-Polymerization Modification of Side-Chain Reactive Polymers

RUI：通过侧链反应性聚合物的聚合后修饰组合合成蛋白质-聚合物缀合物

• 批准号: 2232204
• 负责人: Maren Buck
• 金额: $ 50.42万
• 依托单位: Smith College
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2232204&HistoricalAwards=false
• 关键词: RUI; Combinatorial; Synthesis; Protein; Polymer

Non-technical descriptionLife as we know it would not exist without proteins. Proteins perform functions as wide-ranging as transporting oxygen through the body to recognizing and neutralizing invading microorganisms. Scientists have sought to harness the precise and exquisite functions of proteins to solve a variety of challenges in human health, such as by designing protein drugs that can diagnose and treat disease or by designing new protein scaffolds as part of engineered tissues. Recently, researchers have recognized the power of using chemistry to augment or tailor the functions of proteins by modifying proteins with synthesized molecules. For example, large molecules known as polymers can be linked by chemical bonds to proteins in order to increase the stability of the protein or to tether drug molecules to the protein to create better therapeutics. The goal of this project is to develop a fundamentally new approach for linking proteins to polymers. This approach will improve the efficiency of preparing protein-polymer conjugates (proteins linked to polymers through chemical bonds) for a wide range of applications, including drug delivery. The work will allow the structures of the protein-polymer conjugates to be easily tailored to the needs of specific applications without having to start from scratch. Finally, polymer structures that are degradable in the human body can be coupled to proteins using this method, which is critical for translation to the clinic. To demonstrate the utility of this method, proteins that target cancer cells will be coupled to polymers for the development of new therapeutic structures. The principle investigator will conduct this work in collaboration with a diverse group of undergraduate women to inspire future generations of women researchers. Further, the proposed research will be conducted in an undergraduate organic chemistry laboratory to offer cutting-edge research opportunities to a larger population of women. The principle investigator will also invite graduate students and postdoctoral scholars from nearby research universities to work together to teach undergraduate chemistry courses as a means to train the next generation of college faculty in best pedagogical practices in higher education. Technical descriptionProtein-polymer conjugates couple the exquisite and precise functions of proteins with the wide-ranging functionality of synthetic polymers. These bioconjugates can be used to address important challenges in biotechnology and medicine such as the diagnosis and treatment of disease or engineering new tissues. Protein-polymer conjugates are generally synthesized by polymerizing monomers from protein initiators, termed grafting-from, or by coupling polymers containing a single reactive site at the chain end to specific amino acids on proteins, termed grafting-to. Grafting-from requires that the monomer be water soluble and compatible with the protein structure; these requirements limit the range of chemical functionality that can be incorporated into the structure. Grafting-to suffers from low coupling efficiencies due to the need for two large molecules to react at a single site. In both approaches, new polymer structures must be synthesized each time new bioconjugate structures are desired. This NSF project seeks to directly address these limitations by investigating side-chain reactive polymers for the modular and combinatorial synthesis of protein-polymer conjugates. The proposed work will use a post-polymerization modification strategy to synthesize hydrophilic, side-chain reactive polymers that can be efficiently conjugated to proteins through either amine-activated ester or thiol-maleimide reactions. Side-chain and chain-end reactive polymers will be directly compared to establish side-chain reactive polymers as an alternative to terminally reactive polymers. Side-chain reactive polycarbonates will also be explored for the synthesis of degradable protein-polymer conjugates. The work proposed here will demonstrate efficient, combinatorial routes for protein-polymer-drug conjugate synthesis as well as contribute to the collective understanding of how macromolecular structure influences the function of protein-polymer conjugates.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

我们知道，没有蛋白质将不存在非技术描述。蛋白质的作用与通过人体运输氧气以识别和中和入侵的微生物一样广泛。科学家试图利用蛋白质的精确和精致功能来解决人类健康中的各种挑战，例如设计可以诊断和治疗疾病的蛋白质药物，或通过设计新的蛋白质支架作为工程组织的一部分。最近，研究人员已经认识到使用化学方法通过用合成分子修饰蛋白质来增强或量身定制蛋白质功能的能力。例如，可以通过化学键与蛋白质联系起来的大分子，以提高蛋白质的稳定性或将药物分子链接到蛋白质上，从而产生更好的治疗剂。该项目的目的是开发一种将蛋白质与聚合物联系起来的新方法。这种方法将提高制备蛋白质聚合物偶联物（通过化学键相关的蛋白质）的效率，包括药物递送。这项工作将使蛋白质聚合物共轭物的结构轻松根据特定应用的需求量身定制，而无需从头开始。最后，可以使用这种方法将人体降解的聚合物结构与蛋白质偶联，这对于转化为诊所至关重要。为了证明这种方法的实用性，靶向癌细胞的蛋白质将与聚合物耦合以开发新的治疗结构。原则研究者将与一群多样化的本科妇女合作进行这项工作，以激发子孙后代的女性研究人员。此外，拟议的研究将在本科有机化学实验室中进行，为更多妇女提供尖端的研究机会。这位主要研究者还将邀请附近研究型大学的研究生和博士后学者一起教授本科化学课程，以此作为培训下一代大学教师在高等教育领域的最佳教学实践的手段。技术描述蛋白聚合物偶联蛋白质的精致和精确的功能与合成聚合物的广泛功能。这些生物结合物可用于应对生物技术和医学的重要挑战，例如诊断和治疗疾病或工程新组织。蛋白聚合物偶联物通常是通过从蛋白质引发剂中的聚合单体（称为接枝）的聚合单体合成的，或通过在链上含有单个反应性位点的聚合物耦合到蛋白质上的特异性氨基酸，称为接枝。嫁接from要求单体可溶并与蛋白质结构兼容。这些要求限制了可以合并到结构中的化学功能范围。由于需要两个大分子在一个位点反应，因此嫁接到耦合效率低。在两种方法中，都必须每次需要新的生物缀合物结构时都合成新的聚合物结构。该NSF项目旨在通过研究蛋白聚合物偶联物的模块化和组合合成的侧链反应性聚合物来直接解决这些局限性。拟议的工作将使用后聚合修饰策略来合成亲水性的侧链反应性聚合物，这些聚合物可以通过胺激活的酯或硫醇甲酰亚胺反应有效地与蛋白质有效偶联。将直接比较侧链和链端反应性聚合物，以建立侧链反应性聚合物作为终末反应性聚合物的替代品。还将探索侧链反应性聚碳酸酯，以合成可降解的蛋白质聚合物偶联物。这里提出的工作将证明蛋白质聚合物 - 毒物共轭合成的有效，组合途径，并有助于集体理解大分子分子结构如何影响蛋白质聚合物共轭的功能。该奖项奖通过评估了NSF的法定范围，反映了对经过评估的支持者，并已被评估的知识范围和众所周知。