Understanding the Role of Zwitterionic Polymers or Peptides in the Bioactivity of Conjugated or Fused Proteins

非技术：在不牺牲生物活性的情况下稳定基于蛋白质的治疗方法是蛋白质药物输送的主要挑战。聚乙二醇偶联或聚乙二醇化已被广泛用于提高蛋白质的稳定性，但往往伴随着有害的影响蛋白质的生物活性。目前，许多聚合物-蛋白偶联物的生物活性明显丧失。两性离子材料是保存结合蛋白生物活性的一种很有前途的替代材料。这项工作的目的是获得对生物材料在蛋白质生物活性中的作用的基本理解，当这些生物材料与蛋白质偶联时，开发新的偶联物，提高稳定性，但生物活性损失最小。这项工作的成功将在分子水平上对生物材料与生物分子和大分子的相互作用提供基本的理解，并指导新的蛋白质偶联物的设计用于实际应用。PI将通过已建立的地方项目从代表性不足的群体中招收本科生，并为研究生、本科生和高中生提供多学科研究项目。PI将通过组织国际会议，编辑期刊特刊和促进国际合作来促进两性离子材料领域的发展。技术：与聚乙二醇（PEG）或聚乙二醇化的偶联已广泛用于增加蛋白质的稳定性，但往往伴随着有害的影响蛋白质的生物活性。这项工作的目的是获得对生物材料在聚合物（或肽）-蛋白质偶联物的生物活性中的作用的基本理解，并开发具有更高稳定性，但生物活性损失最小的新偶联物。通过这项工作，将证明与两性离子聚合物（或两性化）或交变电荷EK肽（或乙酰化）结合比聚乙二醇化更能保持蛋白质的生物活性。在这项工作中，将使用几种不同结构，不同类型和明确长度的新型生物材料。干扰素(IFN)- α -2a将被用作这项基础研究的模型蛋白，因为聚乙二醇化(IFN)- α -2a的生物活性仅为其天然形式的7%。这项工作采用了最先进的生物材料和蛋白质偶联方法来解决一个长期存在的问题，即聚乙二醇化后显著的生物活性损失，特别是对于大的结合靶点。PI将通过已建立的地方项目从代表性不足的群体中招收本科生，并为研究生、本科生和高中生提供多学科研究项目。PI将通过组织国际会议，编辑期刊特刊和促进国际合作来促进两性离子材料领域的发展。

Nontechnical: Stabilizing protein-based therapeutics without sacrificing biological activity is a major challenge in the delivery of protein drugs. Conjugation with poly(ethylene glycol) (PEG) or PEGylation has been widely used to increase protein stability, but often accompanies an unwanted detrimental effect on protein bioactivity. At present, many polymer-protein conjugates suffer significant bioactivity loss. Zwitterionic materials are a promising alternative for preserving the bioactivity of conjugated proteins. The objectives of this work are to gain a fundamental understanding of the role of biomaterials in protein bioactivity when these biomaterials are conjugated to proteins and to develop new conjugates with improved stability, but minimum bioactivity loss. The success of this work will provide a fundamental understanding of the interactions of biomaterials with biomolecules and macromolecules at the molecular level and guide the design of new protein-conjugates for practical applications. The PI will recruit undergraduate students from underrepresented groups through established local programs and provide multidisciplinary research projects to graduate students, undergraduate students and high school students. The PI will promote the field of zwitterionic materials through organizing international conferences, editing journal special issues and promoting international collaborations. Technical: Conjugation with poly(ethylene glycol) (PEG) or PEGylation has been widely used to increase protein stability, but often accompanies an unwanted detrimental effect on protein bioactivity. The objectives of this work are to gain a fundamental understanding of the role of biomaterials in the bioactivity of polymer (or peptide)-protein conjugates and to develop new conjugates with improved stability, but minimum bioactivity loss. Through this work, it will be demonstrated that conjugation with zwitterionic polymers (or zwitterlation) or alternating-charge EK peptides (or EKylation) is better than PEGylation to retain protein bioactivity. In this work, several new biomaterials of different architectures, different types, and well-defined lengths will be used. Interferon (IFN)-alfa-2a will be used as a model protein for this fundamental study since the bioactivity of PEGylated (IFN)-alfa-2a is only 7% of its native form. This work employs state-of-the-art biomaterials and protein conjugation methods to solve one long-standing issue, i.e., significant bioactivity loss after PEGylation, particularly for large binding targets. The PI will recruit undergraduate students from underrepresented groups through established local programs and provide multidisciplinary research projects to graduate students, undergraduate students and high school students. The PI will promote the field of zwitterionic materials through organizing international conferences, editing journal special issues and promoting international collaborations.