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

我们所知道的生命如果没有蛋白质就不会存在。蛋白质的功能范围很广，如在体内运输氧气，识别和中和入侵的微生物。科学家们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，例如通过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的力量，通过用合成分子修饰蛋白质来增强或调整蛋白质的功能。例如，被称为聚合物的大分子可以通过化学键与蛋白质连接，以增加蛋白质的稳定性或将药物分子与蛋白质结合以产生更好的治疗方法。该项目的目标是开发一种将蛋白质连接到聚合物的全新方法。这种方法将提高制备蛋白质-聚合物缀合物（通过化学键与聚合物连接的蛋白质）的效率，用于广泛的应用，包括药物递送。这项工作将允许蛋白质-聚合物缀合物的结构容易地根据特定应用的需要进行定制，而不必从头开始。最后，可以使用这种方法将在人体内可降解的聚合物结构与蛋白质偶联，这对于转化为临床至关重要。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偶联，以开发新的治疗结构。主要研究者将与一群不同的女本科生合作开展这项工作，以激励未来几代女性研究人员。此外，拟议的研究将在本科有机化学实验室进行，为更多的女性提供尖端研究机会。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共同教授本科化学课程，作为培养下一代高等教育最佳教学实践的大学教师的一种手段。技术说明蛋白质-聚合物结合物将蛋白质的精致和精确功能与合成聚合物的广泛功能结合起来。这些生物缀合物可用于解决生物技术和医学中的重要挑战，例如疾病的诊断和治疗或工程新组织。蛋白质-聚合物缀合物通常通过使来自蛋白质引发剂的单体聚合来合成，称为接枝，或通过将在链端含有单个反应位点的聚合物偶联到蛋白质上的特定氨基酸来合成，称为接枝。接枝要求单体是水溶性的并且与蛋白质结构相容;这些要求限制了可以并入结构中的化学官能团的范围。由于需要两个大分子在单个位点反应，接枝-to的偶联效率低。在这两种方法中，每当需要新的生物缀合物结构时，必须合成新的聚合物结构。这个NSF项目旨在通过研究用于蛋白质-聚合物缀合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限制。拟议的工作将使用聚合后改性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活化酯或硫醇-马来酰亚胺反应有效地与蛋白质缀合。将直接比较侧链和链端反应性聚合物，以确定侧链反应性聚合物作为末端反应性聚合物的替代品。侧链反应性聚碳酸酯也将被探索用于可降解蛋白质-聚合物缀合物的合成。本文提出的工作将展示蛋白质-聚合物-药物偶联物合成的有效组合路线，并有助于对大分子结构如何影响蛋白质-聚合物偶联物功能的集体理解。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.