Lavie A, Schlichting I, Vetter I R, Konrad M, Reinstein J, Goody R S
Max Planck Institute for Molecular Physiology, Department of Physical Biochemistry, Dortmund, Germany.
Nat Med. 1997 Aug;3(8):922-4. doi: 10.1038/nm0897-922.
Nucleoside-based inhibitors of reverse transcriptase were the first drugs to be used in the chemotherapy of AIDS. After entering the cell, these substances are activated to their triphosphate form by cellular kinases, after which they are potent chain terminators for the growing viral DNA. The two main factors limiting their efficacy are probably interrelated. These are the insufficient degree of reduction of viral load at the commencement of treatment and the emergence of resistant variants of the virus. The reason for the relatively poor suppression of viral replication appears to be inefficient metabolic activation. Thus, for the most extensively used drug, 3'-azido-3'-deoxythymidine (AZT), whereas phosphorylation to the monophosphate is facile, the product is a very poor substrate for the next kinase in the cascade, thymidylate kinase. Because of this, although high concentrations of the monophosphate can be reached in the cell, the achievable concentration of the active triphosphate is several orders of magnitude lower. Determination of the structure of thymidylate kinase as a complex with AZT monophosphate (AZTMP) together with studies on the kinetics of its phosphorylation have now led to a detailed understanding of the reasons for and consequences of the poor substrate properties.
核苷类逆转录酶抑制剂是最早用于艾滋病化疗的药物。进入细胞后，这些物质被细胞激酶激活为三磷酸形式，之后它们成为正在增长的病毒DNA的有效链终止剂。限制其疗效的两个主要因素可能相互关联。这两个因素是治疗开始时病毒载量降低程度不足以及病毒耐药变异体的出现。病毒复制抑制相对较差的原因似乎是代谢激活效率低下。因此，对于使用最广泛的药物3'-叠氮-3'-脱氧胸苷（AZT），虽然磷酸化生成单磷酸很容易，但产物是级联反应中下一个激酶胸苷酸激酶的非常差的底物。因此，尽管细胞中可以达到高浓度的单磷酸，但活性三磷酸的可达到浓度要低几个数量级。胸苷酸激酶与AZT单磷酸（AZTMP）复合物的结构测定以及对其磷酸化动力学的研究，现在已经详细了解了底物性质差的原因和后果。
