Optimizing therapeutic peptide presentation within polymers

项目摘要 对于范围广泛的疾病，多肽可以提供巨大的治疗益处，但半衰期很短 生物环境中多肽的大量存在阻碍了它们转化为临床应用。免疫系统介导的 清除、肾滤过小于20 nm的结构(如多肽)和酶降解都是如此 有助于多肽的短暂半衰期。将多肽偶联到聚合物上可以克服其中的许多问题 障碍和延长半衰期，类似于聚乙二醇INTRONTM的情况，星形聚合物装饰有 蛋白质治疗性干扰素α-2b可延长蛋白质的半衰期，并使其能够用于癌症治疗 和肝炎，以及其他疾病。然而，多肽与聚合物的偶联也可能减损 基本上是从治疗功能出发的。例如，将抗菌肽附着在一个 聚合物降低了对哺乳动物细胞的毒性，但也显著降低了抗菌活性。另一方面 另一方面，将多个抗菌肽连接到一个聚合物链上可以通过使多价 多肽与生物靶标(例如，病原微生物)的相互作用，但也可能导致不受欢迎的毒性 对哺乳动物细胞的影响。这项建议的总体目标和我的研究小组的一个主要推动力是 利用聚合物化学的进步，能够精确控制聚合物组成、相对分子质量 架构和超分子组装，以优化治疗性多肽的呈现。通过改变 的密度和数量，我们的目标是最大限度地发挥功能和 旨在对抗传染病和肌萎缩侧索硬化症的多肽的治疗益处。一 一组偶联物将以抗菌肽为特色，另一组将以我们设计的结合和 分离毒性多(二肽)S通过立体化学驱动参与肌萎缩侧索硬化症 互动。我们将表征聚合肽的大小、形态、表面电荷和稳定性。 共轭变异体，以及与生物靶标的相互作用，以将共轭结构与这些治疗作用连接起来 相关的生物物理特性。在其他情况下，任何排列的多肽的化学修饰都可以 取消预期的功能；在这些情况下，将多肽物理封装在聚合物颗粒中 提供了一个极好的替代方案。通过调节电荷中性基团的百分比和排列 在其他阴离子聚合物中，我们的目标是控制阳离子的稳定性以及阳离子的负载和释放速度 治疗性多肽。总而言之，这些研究将提供关于用 聚合物优化治疗功能，从而加速这一重要的临床实施 治疗学的课程。

Project Summary For a wide range of diseases, peptides could provide immense therapeutic benefit, however the short half-lives of peptides in biological environments hinder their translation to clinical use. Immune system-mediated clearance, renal filtration of structures smaller than 20 nm (such as peptides), and enzymatic degradation all contribute to the short half-lives of peptides. Conjugating peptides to polymers can overcome many of these obstacles and prolong half-life, similarly as in the case of PEG-INTRONTM, a star-shaped polymer decorated with the protein therapeutic interferon alfa-2b that prolongs half-life of the protein and enables its use to treat cancer and hepatitis, among other conditions. However, conjugation of peptides to polymers may also detract substantially from the therapeutic function. For example, attachment of an antimicrobial peptide to one end of a polymer reduces toxicity to mammalian cells, but also markedly reduces antimicrobial activity. On the other hand, attaching multiple antimicrobial peptides to a polymer chain can improve activity by enabling multivalent interactions of peptides with biological targets (e.g., pathogenic microbes), but may also cause undesired toxic effects to mammalian cells. The overall goal of this proposal and a major thrust of my research group is to leverage advances in polymer chemistry that enable precision control of polymer composition, molecular weight, architecture, and supramolecular assembly to optimize presentation of therapeutic peptides. By varying the density and number of peptides pendent to a water-soluble polymer chain, we aim to maximize the function and therapeutic benefit of peptides designed to combat infectious disease and Amyotrophic Lateral Sclerosis. One set of conjugates will feature antimicrobial peptides, and another will feature peptides we designed to bind and sequester toxic poly(dipepetide)s implicated in Amyotrophic Lateral Sclerosis via stereochemistry-driven interactions. We will characterize the size, morphology, surface charge, and stability of the polymer-peptide conjugate variants, and interactions with biological targets to connect conjugate structure to these therapeutically relevant biophysical properties. In other situations, chemical modification of peptides in any arrangement can abrogate the intended function; in these cases, physical encapsulation of the peptides within polymer particles provides an excellent alternative. By modulating both the percentage and arrangement of charge-neutral groups in otherwise anionic polymers, we aim to control the stability, as well as the loading and release rates of cationic therapeutic peptides. Together, these studies will provide critical insight regarding formulating peptides with polymers to optimize therapeutic function and thereby accelerate the clinical implementation of this important class of therapeutics.