Optimizing therapeutic peptide presentation within polymers

项目摘要 对于广泛的疾病，肽可以提供巨大的治疗益处，但是半衰期短， 肽在生物环境中的降解阻碍了它们的临床应用。免疫系统介导 清除率、小于20 nm的结构（如肽）的肾过滤和酶降解， 导致肽的半衰期短。将肽缀合到聚合物可以克服许多这些缺点， 障碍和延长半衰期，类似于PEG-INTRONTM，星形聚合物装饰的情况下， 蛋白质治疗性干扰素α-2b延长了蛋白质半衰期并使其能够用于治疗癌症 和肝炎等疾病。然而，肽与聚合物的缀合也可能减损 基本上是从治疗功能。例如，将抗微生物肽连接到抗微生物肽的一端， 聚合物降低了对哺乳动物细胞的毒性，但也显著降低了抗微生物活性。另 另一方面，将多个抗微生物肽连接到聚合物链上可以通过使多价抗微生物肽能够在聚合物链上形成多个抗微生物肽来提高活性。 肽与生物靶标的相互作用（例如，病原微生物），但也可能引起不希望的毒性 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主要目标是， 利用聚合物化学的进步，能够精确控制聚合物的组成，分子量， 结构和超分子组装以优化治疗肽的呈递。通过改变 密度和数量的肽悬垂到一个水溶性聚合物链，我们的目标是最大限度地发挥功能， 设计用于对抗感染性疾病和肌萎缩侧索硬化症的肽的治疗益处。一 一组结合物将以抗菌肽为特征，另一组将以我们设计的结合肽为特征， 通过立体化学驱动螯合与肌萎缩侧索硬化症有关的毒性聚（二肽） 交互.我们将表征聚合物-肽的大小、形态、表面电荷和稳定性 缀合物变体，以及与生物靶标的相互作用，以将缀合物结构连接到这些治疗上 相关的生物物理特性。在其他情况下，任何排列的肽的化学修饰可以 废除预期功能;在这些情况下，将肽物理封装在聚合物颗粒内 提供了一个很好的选择。通过调节电荷中性基团的百分比和排列 在其它阴离子聚合物中，我们的目标是控制稳定性以及阳离子聚合物的负载和释放速率。 治疗肽。总之，这些研究将提供关于配制肽的关键见解， 聚合物，以优化治疗功能，从而加速这一重要的临床实施 治疗类。

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.