PEPTIDE DEGRADATION IN POLYMER MATRICES

聚合物基质中的肽降解

• 批准号: 6525808
• 负责人: Elizabeth M. Topp
• 金额: $ 21.64万
• 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 2004-07-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6525808
• 关键词: amidation /deamidation; chemical stability; drug delivery systems; intermolecular interaction; oxidation; pharmacokinetics; polymers; protein degradation; protein structure function; proteolysis; slow release drug

Peptide and polypeptide drugs such as interferons, immunoconjugates, tissue plasminogen activator, human growth hormone and erythropoeitin, 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 and protein formulation in polymer matrices for controlled-release applications to the basic mechanistic science involved in degradation reactions in these unusual media. In the first grant period the research has addressed the influence of polymer matrix incorporation on deamidation at Asn "hot spots", one of the most common routes of degradation of peptide and protein pharmaceuticals. Studies proposed for this competing continuation will extend this research to address the effects of peptide and protein secondary structure on deamidation in polymers. In addition, since the findings to date suggest that interactions with polymers may stabilize peptides against deamidation in the solid state, the proposed studies will investigate deamidation of charged peptides in hydrated solid formulations containing ionizable polymers, a system in which stabilization by ionic interactions is anticipated. Finally, the proposed studies will examine the effect of polymer matrix incorporation on oxidation reactions of peptides and proteins, a second class of degradation reaction of considerable practical importance in protein formulation. The principal investigator's experience in the development and characterization of polymeric drug delivery systems will be supplemented by collaborators and co-investigators with expertise in the deamidation and oxidation of peptides and proteins in solution and solid phases, in mechanistic bioorganic chemistry, in the biophysical characterization of protein structure and interactions, and in theoretical approaches to reactivity in solution and solid states.

生物技术革命提供的肽和多肽药物，例如干扰素，免疫偶联物，组织纤溶酶激活剂，人类生长激素和促红细胞生成素，现在正在进入市场，并在药物稳定性和从基础科学技术中呈现挑战的药物科学介绍了药物科学。 该建议将用于控制释放应用的聚合物矩阵中的肽和蛋白质制剂的实际问题与这些异常培养基中降解反应有关的基本机械科学联系起来。在第一个赠款期间，该研究解决了聚合物基质掺入对ASN“热点”脱氨酸的影响，这是肽和蛋白质药物降解的最常见途径之一。 针对这种竞争继续提出的研究将扩展这项研究，以解决肽和蛋白质二级结构对聚合物脱氨酸的影响。 此外，由于迄今为止的发现表明，与聚合物的相互作用可以稳定在固态下脱氨酸的肽，因此拟议的研究将研究在含有可离子聚合物的水合固体配方中的脱氨基，该系统预计将通过离子相互作用稳定在该系统中。 最后，拟议的研究将研究聚合物基质掺入对肽和蛋白质的氧化反应的影响，这是第二类降解反应在蛋白质制剂中相当实用的降解反应。 主要研究者在聚合药物输送系统的开发和表征方面的经验将由合作者和共同投资者补充，在溶液和固体相位的肽和蛋白质在机械生物学化学中的脱氨基和氧化方面的专业知识，在蛋白质结构和互动和互动中的生物物质表征以及对解决方案和反应性和反应性和反应性和反应性和反应性和反应性和反应性和反应性。