McGuigan C, Bellevergue P, Sheeka H, Mahmood N, Hay A J
Welsh School of Pharmacy, University of Wales Cardiff, UK.
FEBS Lett. 1994 Aug 29;351(1):11-4. doi: 10.1016/0014-5793(94)00776-4.
As part of our effort to deliver masked phosphates inside living cells we have discovered that certain phosphate triester derivatives of the inactive nucleoside analogue, dideoxy uridine (ddU) are inhibitors of HIV replication at microM levels. Moreover, we note that certain phosphoramidate derivatives retain their activity in thymidine kinase-deficient cells, which indicates that they do indeed act by intracellular release of the free nucleotide, and that they successfully by-pass the nucleoside kinase. The increased structural freedom in drug design which this allows may have implications for dealing with the emergence of resistance and may stimulate the discovery of improved therapeutic agents.
作为我们向活细胞内递送掩蔽磷酸盐工作的一部分，我们发现，无活性核苷类似物双脱氧尿苷（ddU）的某些磷酸三酯衍生物在微摩尔水平上是HIV复制的抑制剂。此外，我们注意到某些氨基磷酸酯衍生物在胸苷激酶缺陷型细胞中仍保持其活性，这表明它们确实是通过细胞内释放游离核苷酸起作用的，并且它们成功绕过了核苷激酶。这在药物设计中所允许的增加的结构自由度可能对应对耐药性的出现具有重要意义，并可能刺激发现更有效的治疗药物。
