口服给药是最主要的给药途径，但是由于目前药物体外筛选注重与靶受体的亲和性，而导致有的药物性质并不适合口服给药。虽然有时通过给药系统可以克服，但并不都能行得通。肠道中广泛分布的药物转运蛋白以及生物体内广泛分布的氨基肽酶，利用它们为靶点来提高药物的口服吸收是非常有前途的，而且适合我国目前新药创制的条件。本课题以肠寡肽转运蛋白（PEPT1）和嘌呤霉素敏感的氨基肽酶（PSA）为靶点，选择口服吸收差的帕拉米韦（Peramivir）为模型药物，在帕拉米韦的羧基位引入氨基酸，从与PEPT1亲和性和PSA对前药的降解速率两方面对帕拉米韦拟肽类前药进行考察和筛选；结合药物理化和结构参数，建立定量结构-亲和性/降解速率关系，指导前药的合理设计。选择适宜的前药进行大鼠和犬体内药动学研究，考察体内的活化机制、种属差异和药动学行为，并筛选出最佳候选前药。前期工作结果表明本项目可行性良好。

Oral administration was the dominant route for the patient. But, at present, more emphasis has been placed on the affinity of new chemical entities (NCE) to the target receptor during the process of drug development, which lead to the unsuitability for some drugs to oral administration because of the undesirable pharmacokinetic characteristics. The barrier to oral administration could be conquered by a certain drug delivery system. But this strategy was not effective in some circumstance. The intestinal membrane transporters and some aminopeptidases widely expressed in the organism have become promising targets for oral drug delivery. In the present study, some peptidomimetics of peramivir doubly targeted to peptide transporter 1 (PEPT1) and puromycin-sensitive aminopeptidase (PSA) were synthesized by attaching amino acid to the carboxyl group. The peptidomimetics were evaluated by the affinity to PEPT1 and the hydrolysis rate by PSA. To help the rational design of successful prodrugs, the quantitative structure-affinity/hydrolysis rate relationships were constructed by analyzing the physiochemical and structural parameter of the prodrug. The pharmacokinetics of the candidate prodrug was studied in rat and dog to delineate the hydrolysis mechanism, the species difference and the pharmacokinetic behavior. The preliminary result showed the present study was feasible.