Velázquez Sonsoles, de Castro Sonia, Diez-Torrubia Alberto, Balzarini Jan, Camarasa María-José
Institute of Medicinal Chemistry (IQM-CSIC), Juan de la Cierva 3, E-28006 Madrid, Spain.
Curr Med Chem. 2015;22(8):1041-54. doi: 10.2174/0929867322666150114163449.
In the search of novel enzyme-based prodrug approaches to improve pharmacological properties of therapeutic drugs such as solubility and bioavailability, dipeptidyl-peptidase IV (DPP IV, also termed as CD26) enzyme activity provides a previously unexplored successful prodrug strategy. This review covers key aspects of the enzyme useful for the design of CD26-directed prodrugs. The proof-of-concept of this prodrug technology is provided for amine-containing agents by directly linking appropriate di- (or oligo)peptide moieties to a free amino group of a non-peptidic drug through an amide bond which is specifically hydrolized by DPP IV/CD26. Special emphasis is also made in discussing the design and synthesis of more elaborated tripartite prodrug systems, for further extension of the strategy to hydroxy-containing drugs. The application of this technology to improve water solubility and oral bioavailability of prominent examples of antiviral nucleosides is highlighted.
在寻找基于新型酶的前药方法以改善治疗药物的药理性质（如溶解度和生物利用度）的过程中，二肽基肽酶IV（DPP IV，也称为CD26）的酶活性提供了一种此前未被探索的成功前药策略。本综述涵盖了该酶对于设计CD26导向前药有用的关键方面。通过将合适的二（或寡）肽部分通过酰胺键直接连接到非肽类药物的游离氨基上，该酰胺键可被DPP IV/CD26特异性水解，从而为含胺类药物提供了这种前药技术的概念验证。在讨论更复杂的三方前药系统的设计和合成时也给予了特别强调，以便将该策略进一步扩展到含羟基的药物。突出了该技术在改善抗病毒核苷典型实例的水溶性和口服生物利用度方面的应用。
