PEPTIDE DEGRADATION IN POLYMER MATRICES

随着生物技术革命，干扰素、免疫结合物、组织纤溶酶原激活剂、人类生长激素和促红细胞生成素等多肽药物正在进入市场，并向制药科学提出了从基础科学到开发技术的药物稳定性和给药方面的挑战。这项建议将用于控制释放的聚合物基质中的多肽和蛋白质配方的实际问题与涉及这些不寻常介质中的降解反应的基础机械科学联系起来。在第一个赠款期间，这项研究解决了聚合物基质掺入对ASN“热点”脱酰胺化的影响，ASN“热点”是多肽和蛋白质药物最常见的降解途径之一。为这一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中脱酰胺化的影响。此外，由于到目前为止的研究结果表明，与聚合物的相互作用可以稳定多肽在固体状态下的脱酰胺化，拟议的研究将研究含有可电离聚合物的水合固体配方中带电多肽的脱酰胺化，在该体系中，预期通过离子相互作用稳定。最后，建议的研究将考察聚合物基质掺入对肽和蛋白质氧化反应的影响，这是蛋白质配方中具有相当重要实际意义的第二类降解反应。首席研究人员在聚合物药物输送系统的开发和表征方面的经验将得到合作者和合作研究人员的补充，他们在多肽和蛋白质在溶液和固体中的脱酰胺化和氧化、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在溶液和固体中反应的理论方法方面具有专长。

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.