Protein-Piperazine Polymer Conjugates as a New Platform for Oral Protein Therapy

摘要：本研究计划将使患者口服蛋白质药物。尽管患者最愿意并且能够口服药物，但目前对于胰岛素等蛋白质疗法来说，这是不可能的。阻止口服蛋白质给药的最大挑战是蛋白质药物太大，无法通过小肠进入血液并发挥作用。这项研究将通过制造化学修饰的蛋白质来克服这一挑战，这种蛋白质可以暂时使肠道更多孔，从而使蛋白质药物可以被吸收。化学修饰将由从蛋白质表面延伸出来的聚合物链组成。我们将学习聚合物的化学成分如何改善药物进入血液的运输，并优化化学成分以获得最大的治疗效果。结果将公布供公众传播。拟议的推广计划将惠及所有年龄段的学生，包括1500多名K-12匹兹堡学生，他们将从动手科学演示中学习。本科生和研究生将被培养为下一代工程师，重点是为女性和代表性不足的少数民族提供研究机会。技术摘要：本研究计划将为口服蛋白质递送疗法建立一个新的范式。口服蛋白质递送是当今医学中最紧迫的未满足需求之一，它的实现将对患者的依从性和蛋白质治疗的可及性产生巨大影响。不幸的是，由于一些挑战，口服蛋白递送尚未实现，其中最重要的是治疗蛋白无法穿过肠上皮进入血液。这项工作将通过蛋白质-聚合物偶联物的工程设计，选择性地增强肠道蛋白质的通透性，使口服蛋白质递送成为可能。含有增强渗透侧链的聚合物将从治疗相关酶，天冬酰胺酶的表面生长。侧链将包含哌嗪衍生物，这是PI先前显示的一类分子，具有出色的渗透增强作用而没有细胞毒性。该研究将确定结构-功能关系，以帮助合理设计和阐明渗透增强的分子机制。在NSF资助期结束时，这种首创的平台技术将被很好地应用于其他治疗性蛋白质，包括酶和抗体。结果将公布供公众传播。拟议的外展计划将使所有年龄段的学生受益，包括每年超过1500名K-12匹兹堡学生，他们将学习动手给药模块。通过生物运输和药物输送机制方面的技术培训，将本科生和研究生培养成有生产力、有影响力的未来工程师，重点是为妇女和代表性不足的少数群体提供研究机会。该奖项反映了美国国家科学基金会的法定使命，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 Abstract:This research plan will enable patients to take protein medications orally. Although patients are most willing and able to take their medications by mouth, this is not currently possible for protein therapeutics like insulin. The most significant challenge preventing oral protein delivery is that the protein drugs are too large to exit the small intestine and enter the bloodstream where they take effect. This research will overcome that challenge by creating chemically modified proteins that temporarily make the intestines more porous so that the protein drug can be absorbed. The chemical modification will consist of polymer chains extending from the surface of the protein. We will learn how the chemistry of the polymer improves the transport of the medicine into the bloodstream and optimize the chemistry for the maximum therapeutic effect. Results will be published for public dissemination. The proposed outreach plan will benefit students of all age levels, including over 1500 K-12 Pittsburgh students who will learn from hands-on science demonstrations. Undergraduate and graduate students will be trained as the next generation of engineers, with an emphasis on research opportunities for women and underrepresented minorities.Technical Abstract:This research plan will establish a new paradigm for oral protein delivery therapeutics. Oral protein delivery is one of the most pressing unmet needs in medicine today, and its realization would have dramatic effects on patient compliance and the accessibility of protein therapeutics. Unfortunately, oral protein delivery has not yet been realized due to several challenges, the most significant of which is the inability of therapeutic proteins to cross the intestinal epithelium into the bloodstream. This work will enable oral protein delivery through the engineering of protein-polymer conjugates that selectively enhance intestinal protein permeability. Polymers containing permeation-enhancing side chains will be grown from the surface of the therapeutically relevant enzyme, asparaginase. The side chains will contain piperazine derivatives, a class of molecules previously shown by the PI to offer excellent permeation enhancement without cytotoxicity. The proposed research will determine structure-function relationships to aid in rational design and elucidate the molecular mechanisms of permeation enhancement. At the end of the NSF grant period, this first-of-its-kind platform technology will be well-poised for application to additional therapeutic proteins, including enzymes and antibodies. Results will be published for public dissemination. The proposed outreach plan will benefit students of all age levels, including over 1500 K-12 Pittsburgh students each year who will learn from hands-on drug delivery modules. Undergraduate and graduate students will be groomed as productive, influential future engineers through technical training in biological transport and drug delivery mechanisms, with an emphasis on research opportunities for women and underrepresented minorities.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.