PEPTIDE DEGRADATION IN POLYMER MATRICES

生物技术革命带来的干扰素、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等肽和多肽药物现已进入市场，给制药科学带来了从基础科学到开发技术的药物稳定性和递送方面的挑战。 该提案将用于控释应用的聚合物基质中肽和蛋白质配方的实际问题与这些不寻常介质中降解反应所涉及的基础机械科学联系起来。在第一个资助期内，该研究解决了聚合物基质掺入对 Asn“热点”脱酰胺的影响，这是肽和蛋白质药物最常见的降解途径之一。 为这一竞争性延续而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酰胺的影响。 此外，由于迄今为止的研究结果表明，与聚合物的相互作用可以稳定肽以防止固态脱酰胺，因此拟议的研究将研究含有可电离聚合物的水合固体制剂中带电肽的脱酰胺，这是一个预计通过离子相互作用实现稳定的系统。 最后，拟议的研究将检查聚合物基质掺入对肽和蛋白质氧化反应的影响，这是在蛋白质配方中具有相当实际重要性的第二类降解反应。 主要研究者在聚合物药物递送系统的开发和表征方面的经验将得到在溶液和固相中肽和蛋白质的脱酰胺和氧化、机械生物有机化学、蛋白质结构和相互作用的生物物理表征以及溶液和固态反应性的理论方法方面的专业知识的合作者和共同研究者的补充。

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.