PEPTIDE DEGRADATION IN POLYMER MATRICES

描述(改编自《研究人员摘要》)：多肽和多肽 干扰素、免疫结合物、组织型纤溶酶原激活剂、 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呈现 在药物稳定性和给药方面面临挑战的制药科学 范围从基础科学到开发技术。此建议书链接 多肽在聚合物基质中配方的实际问题 控释应用(并将导致以后对蛋白质的研究 类似的环境)中涉及的基本机械科学 蛋白质和多肽在这些不寻常的介质中的降解。这群人 将研究多肽和蛋白质降解的化学系统学在 用于控释制剂的聚合物骨架和 代表性介质对降解速率和降解机理的影响 在ASN和Asp的“热点”中，最常见的实际上 多肽和蛋白质类药物降解的重要途径。这个 模型降解过程中的动力学和产物组成 天冬氨酸-六肽，VYPNGA，来自ACTH中的一个序列，将在 来自聚乙烯醇(PVA)的水凝胶和干凝胶 聚乙烯吡咯烷酮(PVP)冻干制剂。对于矩阵而言， 表现出稳定或加速效应，数量上 将建立降解率和水含量之间的关系， 矩阵将通过它们的玻璃化转变来表征 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 中间体，中间体(通过18O交换)和产物 环开度与pH、缓冲液特性和 浓度和温度。环形成的过渡态将 通过微观的反转来接近，胺对 环酰亚胺。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来检验。模型 化合物也将在聚合物基质中进行检查，发现 对天冬氨酸六肽感兴趣。首席调查员的经验 在定量机械生物有机化学领域将是 辅以具有以下专业知识的合作者和合作调查员 多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 聚合物科学方法的聚合物基质，以及在理论上 接近玻璃状态。

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.