McGuigan C, Kinchington D, Wang M F, Nicholls S R, Nickson C, Galpin S, Jeffries D J, O'Connor T J
Department of Chemistry, University of Southampton, Highfield, UK.
FEBS Lett. 1993 May 17;322(3):249-52. doi: 10.1016/0014-5793(93)81580-s.
Nucleoside analogues previously found to be inactive against the human immunodeficiency virus (HIV) may be activated by simple chemical derivatisation. As part of our effort to deliver masked phosphates inside living cells we have discovered that certain phosphate triester derivatives of inactive nucleoside analogues become inhibitors of HIV replication. This discovery underlies the importance of the masked phosphate approach, and has significant implications for the future design of chemotherapeutic nucleoside analogues. If highly modified nucleoside analogues may be active without the intervention of nucleoside kinase enzymes, major advantage may accrue in terms of low toxicity and enhanced selectivity. Moreover, the increased structural freedom may have implications for dealing with the emergence of resistance. The concept herein described as 'kinase bypass' may thus stimulate the discovery of a new generation of antiviral agents.
先前发现对人类免疫缺陷病毒（HIV）无活性的核苷类似物，可通过简单的化学衍生化作用被激活。作为我们向活细胞内递送掩蔽型磷酸盐努力的一部分，我们发现无活性核苷类似物的某些磷酸三酯衍生物可成为HIV复制的抑制剂。这一发现凸显了掩蔽型磷酸盐方法的重要性，并对未来化疗用核苷类似物的设计具有重大意义。如果高度修饰的核苷类似物在没有核苷激酶酶干预的情况下仍可能具有活性，那么在低毒性和增强选择性方面可能会带来重大优势。此外，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。因此，本文所述的“激酶旁路”概念可能会推动新一代抗病毒药物的发现。
