Instituto de Química Médica (IQM), Consejo Superior de Investigaciones Científicas (CSIC), Juan de la Cierva 3, 28006, Madrid, Spain.
ChemMedChem. 2018 Sep 19;13(18):1885-1889. doi: 10.1002/cmdc.201800454. Epub 2018 Aug 27.
Synthetic nucleosides, designed to mimic naturally occurring nucleosides, are important antiviral and anticancer chemotherapeutic agents. However, nucleosides are not active as such and need to be metabolized, step by step, to their corresponding active nucleoside triphosphates (NTPs). This is mediated by phosphorylating enzymes, mainly host cellular kinases with strong specificity for their substrates; in many cases, this specificity prevents efficient conversion into the NTPs. To circumvent this metabolic handicap, successful nucleo(s/t)ide prodrugs have been developed as a valuable concept in the design of effective drugs. The unique concept of the TriPPPro approach, developed by Chris Meier and colleagues, is a powerful tool for the intracellular delivery of active NTPs, bypassing all the phosphorylation steps required by nucleosides to yield the active NTP metabolites. This concept is illustrated herein with general examples.
合成核苷类似物是一类重要的抗病毒和抗癌化疗药物，设计用于模拟天然存在的核苷。然而，核苷本身没有活性，需要逐步代谢为相应的活性核苷三磷酸（NTP）。这一过程由磷酸化酶介导，主要是宿主细胞激酶，它们对底物具有很强的特异性；在许多情况下，这种特异性阻止了有效转化为 NTP。为了克服这种代谢障碍，成功的核苷（s/t）前药已被开发为设计有效药物的一个有价值的概念。克里斯·迈尔（Chris Meier）及其同事开发的 TriPPPro 方法的独特概念是一种用于细胞内递呈活性 NTP 的强大工具，绕过了核苷产生活性 NTP 代谢物所需的所有磷酸化步骤。本文通过一般实例说明了这一概念。
