Slusarczyk Magdalena, Serpi Michaela, Pertusati Fabrizio
School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK.
Antivir Chem Chemother. 2018 Jan-Dec;26:2040206618775243. doi: 10.1177/2040206618775243.
Following the first report on the nucleoside phosphoramidate (ProTide) prodrug approach in 1990 by Chris McGuigan, the extensive investigation of ProTide technology has begun in many laboratories. Designed with aim to overcome limitations and the key resistance mechanisms associated with nucleoside analogues used in the clinic (poor cellular uptake, poor conversion to the 5'-monophosphate form), the ProTide approach has been successfully applied to a vast number of nucleoside analogues with antiviral and anticancer activity. ProTides consist of a 5'-nucleoside monophosphate in which the two hydroxyl groups are masked with an amino acid ester and an aryloxy component which once in the cell is enzymatically metabolized to deliver free 5'-monophosphate, which is further transformed to the active 5'-triphosphate form of the nucleoside analogue. In this review, the seminal contribution of Chris McGuigan's research to this field is presented. His technology proved to be extremely successful in drug discovery and has led to two Food and Drug Administration-approved antiviral agents.
1990年克里斯·麦奎根首次报道了核苷亚磷酰胺酯（前药）方法后，许多实验室开始对前药技术进行广泛研究。前药方法旨在克服与临床使用的核苷类似物相关的局限性和关键耐药机制（细胞摄取差、转化为5'-单磷酸形式的能力差），已成功应用于大量具有抗病毒和抗癌活性的核苷类似物。前药由一个5'-核苷单磷酸组成，其中两个羟基被氨基酸酯和芳氧基成分掩盖，一旦进入细胞，该成分会被酶代谢以释放游离的5'-单磷酸，进而进一步转化为核苷类似物的活性5'-三磷酸形式。在这篇综述中，介绍了克里斯·麦奎根的研究对该领域的开创性贡献。他的技术在药物研发中被证明极其成功，并促成了两种获得美国食品药品监督管理局批准的抗病毒药物。
