Optimizing therapeutic peptide presentation within polymers

优化聚合物内治疗性肽的呈现

• 批准号: 10654058
• 负责人: Rachel Letteri
• 金额: $ 36.61万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654058
• 关键词: Acceleration; Affinity; Amyotrophic Lateral Sclerosis; Architecture; Binding; Biological; Biological Process; Charge; Chemicals; Clinical; Communicable Diseases; Disease; Encapsulated; Environment; Filtration; Formulation; Goals; Half-Life; Hepatitis; Immune system; Interferon Alfa-2b; Investigation; Kidney; Malignant Neoplasms; Mammalian Cell; Mediating; Modification; Molecular; Molecular Weight; Morphology; Peptides; Polymer Chemistry; Polymers; Proteins; Research; Shapes; Structure; Surface; Therapeutic; Toxic effect; Translations; Variant; Water; antimicrobial; antimicrobial peptide; biophysical properties; clinical implementation; combat; density; design; improved; insight; particle; pathogenic microbe; peptide drug; stereochemistry; therapeutic protein

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.

项目概要 对于多种疾病，肽可以提供巨大的治疗益处，但半衰期较短 生物环境中肽的变化阻碍了它们向临床应用的转化。免疫系统介导 清除、小于 20 nm 的结构（例如肽）的肾过滤以及酶降解 导致肽的半衰期较短。将肽与聚合物缀合可以克服其中的许多问题 障碍并延长半衰期，与 PEG-INTRONTM 的情况类似，PEG-INTRONTM 是一种用 蛋白质治疗干扰素 alfa-2b 可延长蛋白质的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会降低 主要来自于治疗功能。例如，将抗菌肽附着到 聚合物降低了对哺乳动物细胞的毒性，但也显着降低了抗菌活性。另一方面 另一方面，将多种抗菌肽连接到聚合物链上可以通过启用多价来提高活性 肽与生物靶标（例如病原微生物）的相互作用，但也可能导致不良的毒性 对哺乳动物细胞的影响。该提案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成分、分子量、 结构和超分子组装以优化治疗性肽的呈现。通过改变 水溶性聚合物链上的肽的密度和数量，我们的目标是最大化功能和 旨在对抗传染病和肌萎缩侧索硬化症的肽的治疗益处。一 一组缀合物将具有抗菌肽，另一组缀合物将具有我们设计用于结合和 通过立体化学驱动隔离与肌萎缩侧索硬化症有关的有毒聚（二肽） 互动。我们将表征聚合物-肽的尺寸、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都可以 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 提供了一个绝佳的替代方案。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，我们的目标是控制稳定性以及阳离子的负载和释放速率 治疗性肽。总之，这些研究将为配制肽提供重要的见解 聚合物优化治疗功能，从而加速这一重要的临床实施 类疗法。