INHIBITION OF RIBONUCLEOTIDE REDUCTASE BY 2'-SUBSTITUTED DEOXYCYTIDINE ANALOGS - POSSIBLE APPLICATION IN AIDS TREATMENT
INHIBITION OF RIBONUCLEOTIDE REDUCTASE BY 2'-SUBSTITUTED DEOXYCYTIDINE ANALOGS - POSSIBLE APPLICATION IN AIDS TREATMENT
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DOI：
10.1073/pnas.91.18.8403
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发表时间：
1994-08-30
影响因子：
11.1
通讯作者：
REICHARD, P
中科院分区：
文献类型：
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作者：
BIANCHI, V;BORELLA, S;REICHARD, P
在磷酸化为相应的二磷酸后，2 '-叠氮基-2'-脱氧胞苷和2 '-二氟胞苷作为核糖核苷酸还原酶的强效抑制剂。磷酸化需要脱氧胞苷激酶，一种在淋巴细胞中具有特别高活性的酶。因此，可以预期脱氧胞苷类似物对淋巴系统具有一定特异性地抑制还原酶。用类似物预处理人CEM淋巴母细胞显著增加了3 '-脱氧-3'-叠氮胸苷（AzT）的磷酸化。AzT的磷酸化增加是由细胞周期的S期延长引起的。我们的研究结果表明，2 '-取代的脱氧胞苷类似物与AzT的组合在治疗艾滋病的可能性。Gao等人[Gao，W.-是的，卡拉，A.，加洛河C. &洛里，F.等人（1993）Proc. Natl; Acad. Sci. USA 90，8925-8928]已经建议使用核糖核苷酸还原酶抑制剂羟基脲用于此目的，因为所导致的脱氧核糖核苷酸库大小的减小降低了HIV逆转录酶的持续合成能力。从我们的结果来看，2 '-取代的脱氧胞苷类似物可能优于羟基脲。
After phosphorylation to the corresponding diphosphates, 2'-azido-2'-deoxycytidine and 2'-difluorocytidine act as powerful inhibitors of ribonucleotide reductase. Phosphorylation requires deoxycytidine kinase, an enzyme with particularly high activity in lymphoid cells. Therefore, the deoxycytidine analogs can be expected to inhibit the reductase with some specificity for the lymphoid system. Pretreatment of human CEM lymphoblasts with the analogs considerably increased the phosphorylation of 3'-deoxy-3'-azidothymidine (AzT). The increased phosphorylation of AzT is caused by a prolongation of the S phase of the cell cycle. Our results suggest the possibility of a combination of 2'-substituted deoxycytidine analogs with AzT in the treatment of AIDS. Gao et al. [Gao, W.-Y., Cara, A., Gallo, R. C. & Lori, F. (1993) Proc. Natl; Acad. Sci. USA 90, 8925-8928] have suggested the use of the ribonucleotide reductase inhibitor hydroxyurea for this purpose, since the resulting decrease in the size of deoxyribonucleotide pools decreases the processivity of the HIV reverse transcriptase. From our results it would appear that the 2'-substituted deoxycytidine analogs might be preferable to hydroxyurea.