Gong Y F, Srinivas R V, Fridland A
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
Mol Pharmacol. 1993 Jul;44(1):30-6.
The antiviral activity of the purine dideoxynucleosides 2',3'-dideoxyadenosine (ddA) and 2',3'-dideoxyinosine (ddI) is dependent on their conversion into ddA triphosphate in vivo. 5-Amino-4-imidazolecarboxamide riboside (AICA riboside), a natural metabolite in purine biosynthetic pathways, is converted into IMP, a substrate for the biosynthesis of adenine and guanine nucleotides, and enhances the intracellular purine nucleotide pools. Because IMP also serves as a phosphate donor in the anabolic phosphorylation of ddI (and ddA) into ddI monophosphate by the cytosolic enzyme 5'-nucleotidase, we investigated the effects of AICA riboside on the phosphorylation and antiretroviral activity of these purine nucleoside analogs. At an AICA riboside concentration of 0.5 mM, there was a approximately 2-fold increase in the intracellular ATP and GTP levels, whereas a nearly 8-fold increase was observed for the phosphorylation of ddA (or ddI). A marked reduction in intracellular pools of the pyrimidine nucleotides CTP and UTP was observed in AICA riboside-treated cells and inhibited cell proliferation. However, this growth inhibition was prevented by the addition of uridine to the cultures. Cells pretreated with AICA riboside and ddI were less susceptible to human immunodeficiency virus (HIV) infection and synthesized reduced levels of HIV proviral DNA. A 10-fold potentiation of the effectiveness of ddI against both wild-type HIV (HIVIIIB) and a ddI-resistant variant HIV was observed in the presence of 0.5 mM AICA riboside. These results show that AICA riboside modulates the anabolism and antiviral activity of ddI, and they have implications for possible therapies with dideoxynucleosides.
嘌呤双脱氧核苷2',3'-双脱氧腺苷（ddA）和2',3'-双脱氧肌苷（ddI）的抗病毒活性取决于它们在体内转化为三磷酸双脱氧腺苷（ddATP）的过程。5-氨基-4-咪唑甲酰胺核糖核苷（AICA riboside）是嘌呤生物合成途径中的一种天然代谢产物，可转化为次黄嘌呤核苷酸（IMP），后者是腺嘌呤和鸟嘌呤核苷酸生物合成的底物，能增加细胞内嘌呤核苷酸池。由于IMP在胞质酶5'-核苷酸酶将ddI（和ddA）合成代谢磷酸化为单磷酸双脱氧肌苷（ddIMP）的过程中也作为磷酸供体，我们研究了AICA riboside对这些嘌呤核苷类似物磷酸化及抗逆转录病毒活性的影响。在AICA riboside浓度为0.5 mM时，细胞内ATP和GTP水平约增加2倍，而ddA（或ddI）的磷酸化水平增加近8倍。在AICA riboside处理的细胞中观察到嘧啶核苷酸CTP和UTP的细胞内池显著减少，细胞增殖受到抑制。然而，向培养物中添加尿苷可防止这种生长抑制。用AICA riboside和ddI预处理的细胞对人免疫缺陷病毒（HIV）感染的敏感性较低，且HIV前病毒DNA的合成水平降低。在存在0.5 mM AICA riboside的情况下，观察到ddI对野生型HIV（HIVIIIB）和ddI耐药的HIV变异株的有效性增强了10倍。这些结果表明，AICA riboside调节ddI的合成代谢和抗病毒活性，对双脱氧核苷的可能治疗具有重要意义。
