INHIBITORS OF IMP DEHYDROGENASE STIMULATE THE PHOSPHORYLATION OF THE ANTIVIRAL NUCLEOSIDE 2',3'-DIDEOXYGUANOSINE
INHIBITORS OF IMP DEHYDROGENASE STIMULATE THE PHOSPHORYLATION OF THE ANTIVIRAL NUCLEOSIDE 2',3'-DIDEOXYGUANOSINE
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DOI：
10.1016/0006-291x(90)90827-a
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发表时间：
1990-09-28
影响因子：
3.1
通讯作者：
FRIDLAND, A
中科院分区：
文献类型：
--
作者：
AHLUWALIA, G;COONEY, DA;FRIDLAND, A
在人类T细胞培养系统（Molt-4细胞）中，发现肌苷酸脱氢酶（IMPD）抑制剂病毒唑、硫唑弗林和麦考酚酸可刺激抗HIV药物2 '，3'双脱氧鸟苷合成代谢为其5 '-二磷酸（ddGDP）的20倍。进一步转化为ddGTP（药物的活性形式）的刺激幅度较小，但仍然非常显著（在适当浓度的利巴韦林或硫唑福林下高达4倍）。在这些增加的同时，抑制剂也使IMP水平增加高达35倍。这些结果支持这样的假设，即ddGuo的初始磷酸化是由磷酸转移酶（5′-核苷酸酶）催化的，该磷酸转移酶利用IMP作为其磷酸供体（约翰逊和弗里德兰，[1989]莫莱克. Pharmacol. 36，291-295）。伴随着ddGuo 5′-磷酸化的增加，当该试剂与利巴韦林（5μM）在CEM细胞试验系统中联合使用时，观察到其抗HIV活性增加高达6.5倍。
The inosinate dehydrogenase (IMPD) inhibitors ribavirin, tiazofurin and mycophenolic acid were found to stimulate by as much as 20-fold the anabolism of the anti-HIV agent 2′,3′dideoxyguanosine to its 5′-diphosphate (ddGDP) in a human T-cell culture system (Molt-4 cells). Stimulation of the further conversion to ddGTP (the active form of the drug) was lesser in magnitude but still highly significant (up to 4-fold at appropriate concentrations of ribavirin or tiazofurin). In parallel with these increases, the inhibitors also produced increases of up to 35-fold in IMP levels. These results support the proposal that the initial phosphorylation of ddGuo is catalyzed by a phosphotransferase (5′-nucleotidase) which utilizes IMP as its phosphate donor (Johnson and Fridland, [1989] Molec. Pharmacol. 36, 291–295). Concomitant with this increase in 5′-phosphorylation of ddGuo, an increase in its anti-HIV activity of up to 6.5-fold was observed when this agent was combined with ribavirin (5μM) in the CEM cell assay system.