PEPTIDE DEGRADATION IN POLYMER MATRICES

聚合物基质中的肽降解

• 批准号: 2398131
• 负责人: RICHARD L. SCHOWEN
• 金额: $ 18.95万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2398131
• 关键词: biotransformation; chemical models; chemical reaction; chemical stability; drug delivery systems; hydropathy; pharmacokinetics; polymers; protein degradation; proteolysis; slow release drug

DESCRIPTION (Adapted from Investigator's Abstract): Peptide and polypeptide drugs such as interferons, immunoconjugates, tissue plasminogen activator, human growth hormone, and erythropoietin, made available by the biotechnological revolution, are now entering the marketplace and presenting pharmaceutical science with challenges in drug stability and delivery that range from basic science to developmental technology. This proposal links the practical problem of peptide formulation in polymer matrices for controlled-release applications (and will lead to later work on proteins in similar environments) to the basic mechanistic science involved in degradation of proteins and peptides in these unusual media. This group will study the chemical systematics of peptide and protein degradation in polymeric matrices used for controlled-release formulations and the influence of representative media on the rates and mechanisms of degradation at Asn and Asp "hot spots," one of the most common of the practically important routes of degradation of peptide and protein pharmaceuticals. The kinetics and product composition in the degradation of a model Asn-hexapeptide, VYPNGA, derived from a sequence in ACTH, will be studied in hydrogels and xerogels derived from polyvinyl alcohol (PVA) and in lyophilized preparations of polyvinyl pyrrolidone (PVP). For matrices that exhibit either stabilizing or accelerating effects, quantitative relationships will be developed between degradation rates and water content, and the matrices will be characterized by their glass transition temperatures, activity of water, differential scanning calorimetry, and nuclear magnetic resonance. Small-molecule models of the cyclic-imide intermediate that mediates intermediates (by 18O exchange), and product ratios in ring opening as a function of pH, buffer identity and concentration, and temperature. Transition states for ring formation will be approached through the microscopic reverse, the attack of amines on the cyclic imide. Steric, electronic and intramolecular catalytic effects will be examined by structural variation of the model compounds. The model compounds will also be examined in polymeric matrices found to be of interest with the Asn hexapeptide. The principal investigator's experience in the field of quantitative mechanistic bioorganic chemistry will be supplemented by collaborators and co-investigators with expertise in the degradation of peptides and proteins in solution and solid phases, in polymeric controlled-release formulations, in the characterization of polymeric matrices by polymer-science approaches, and in theoretical approaches to the glassy state.

描述（改编自研究者摘要）：肽和多肽 药物如干扰素、免疫缀合物、组织纤溶酶原激活剂， 人类生长激素和促红细胞生成素，由 生物技术革命，现在正在进入市场，并提出 制药科学在药物稳定性和递送方面面临挑战， 从基础科学到发展技术。 这一提议将 在聚合物基质中肽制剂实际问题 控释应用（并将导致以后的蛋白质工作， 类似的环境）的基本机械科学涉及 蛋白质和肽在这些不寻常的介质中的降解。 这群 将研究肽和蛋白质降解的化学系统学， 用于控制释放制剂的聚合物基质， 代表性介质对降解速率和机制的影响 在Asn和Asp的“热点”，一个最常见的实际 肽和蛋白质药物降解的重要途径。 的 模型降解的动力学和产物组成 Asn-六肽，VYPNGA，来源于ACTH序列，将在 衍生自聚乙烯醇（PVA）的水凝胶和干凝胶， 聚乙烯吡咯烷酮（PVP）的冻干制剂。 对于 表现出稳定或加速的效果，定量的 将在降解速率和含水量之间建立关系， 并且基质的特征在于它们的玻璃化转变 温度、水的活度、差示扫描量热法，以及 核磁共振 环酰亚胺的小分子模型 介导中间体（通过18 O交换）和产物的中间体 开环中的比率作为pH、缓冲液特性和 浓度和温度。 环形成的过渡态将 通过显微镜反向接近，胺对 环亚胺 空间、电子和分子内催化效应将 通过模型化合物的结构变化进行检查。 模型 还将在聚合物基质中检查化合物， 对Asn六肽感兴趣。 主要研究者的经验 在定量机械生物有机化学领域， 由具有以下方面专门知识的合作者和共同调查者予以补充： 肽和蛋白质在溶液和固相中的降解， 聚合物控释制剂，在表征 聚合物矩阵的聚合物科学方法，并在理论上 接近玻璃态。