Control of biopharmaceutical properties of peptide drugs by chemical modification employing carbohydrates

多肽类药物的化学修饰是控制和改善其生物药剂学性质的一种很有前途的方法。为了建立一个系统的策略，这种方法，我们已经调查了化学结构，物理化学和生物学特性之间的关系，和系统的处置特点。这些研究包括通过引入电荷、碳水化合物部分和增加总分子大小或阻碍特异性生物识别的大分子进行修饰。尤其是糖类衍生物的利用，肾脏的肾小球滤过、肝脏的摄取和蛋白酶的降解是决定蛋白质类药物体内分布特征的主要过程。我们已经成功地克服了这些问题，并通过利用与葡聚糖和聚阴离子羧甲基葡聚糖的缀合来延长肽的生物半衰期。通过应用这些方法，尿酸酶、超氧化物歧化酶和大豆胰蛋白酶抑制剂的生物半衰期和治疗活性得到显着延长。另一方面，半乳糖或甘露糖的引入通过受体介导的内吞作用增强器官摄取。这些观察结果将为建立控制肽类药物体内命运的方法提供重要的基础信息。

Chemical modification of peptide drugs seems to be a promising way to control and improve their biopharmaceutical properties. In order to establish a systematic strategy for this approach, we have investigated relationships between chemical structures, physicochemical and biological properties, and systemic disposition characteristics. These studies include modifications via introduction of electric charge, carbohydrate moiety, and macromolecules which increase total molecular size or hinder specific biological recognition. Especially, studies were focused on the utilization of carbohydrate derivatives.Glomerular filtration in the kidney, hepatic uptake, and degradation by a protease are major processes which determine in vivo disposition features of proteinous drugs. We have succeeded to overcome these problems and prolong biological half-lives of peptides by utilizing the conjugation with dextran and polyanionic carboxymethyl-dextran. By applying these-methods, remarkable prolongation of biological half-life and therapeutic activity was obtained for uricase, superoxide dismutase, and soybean trypsin inhibitor. On the other hand, introduction of galactose or mannose enhanced organ uptake via receptor-mediated endocytosis. Those observations would offer important basic information for establishing a methodology of controlling in vivo fate of peptide drugs.