Mechanism of anti-human immunodeficiency virus activity of beta-D-6-cyclopropylamino-2',3'-didehydro-2',3'-dideoxyguanosine.
Mechanism of anti-human immunodeficiency virus activity of beta-D-6-cyclopropylamino-2',3'-didehydro-2',3'-dideoxyguanosine.
复制标题
β-D-6-环丙氨基-2,3-二脱氢-2,3-二脱氧鸟苷的抗人类免疫缺陷病毒活性机制。
DOI：
10.1128/aac.49.5.1994-2001.2005
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发表时间：
2005
影响因子：
4.9
通讯作者：
Ander
中科院分区：
文献类型：
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作者：
Ray,AdrianS;Hernandez-Santiago,BrendaI;Mathew,JudyS;Murakami,Eisuke;Bozeman,Carey;Xie,Meng-Yu;Dutschman,GingerE;Gullen,Elizabeth;Yang,Zhenjun;Hurwitz,Selwyn;Cheng,Yung-Chi;Chu,ChungK;McClure,Harold;Schinazi,RaymondF;Ander
为了更好地了解靶向人类免疫缺陷病毒（HIV）的平面不饱和核苷类似物核糖环中氧的重要性，合成了2',3'-二脱氢-2',3'-二脱氧鸟苷（cyclo-d4G）的6-环丙基取代前药，并研究了其细胞代谢、抗病毒活性和药代动力学行为。 Cyclo-d4G 在原代血液单核细胞 (PBMC) 中具有选择性抗 HIV 活性，在 1.1 ± 0.1 μM 浓度下可有效抑制 HIV-1 LAI 株 50%，同时在 84.5 μM 浓度下可抑制 50% 的细胞活力。 PBMC 中的抗病毒活性并未受到 184 位蛋氨酸突变为缬氨酸或病毒逆转录酶中胸苷相关突变的显着影响。亮氨酸 74 突变为缬氨酸以及赖氨酸 65 突变为精氨酸具有轻度至中度耐药性（高达五倍）。描述细胞代谢和环-d4G 激活机制的研究表明，在腺苷/腺苷酸脱氨酶抑制剂 2'-脱氧考福霉素存在下，抑制病毒复制的效力降低，这意味着抗病毒活性是由于其代谢为 2'-dGTP 类似物 d4GTP。糖分解代谢物的细胞内形成说明了 d4G 中糖苷键的化学和潜在的酶促不稳定性。进一步的研究表明，cyclo-d4G 具有新的细胞内磷酸化途径。在神经元细胞中，Cyclo-d4G 比 2',3'-二脱氧胞苷和 2',3'-二脱氢-3'-脱氧胸苷引起线粒体毒性的可能性更低。此外，cyclo-d4G 与许多目前使用的抗 HIV 药物具有有利的协同作用。在恒河猴中观察到的口服生物利用度差可能是由于不稳定的糖苷键，并且口服给药可能需要特殊的制剂。
To better understand the importance of the oxygen in the ribose ring of planar unsaturated nucleoside analogs that target human immunodeficiency virus (HIV), a 6-cyclopropyl-substituted prodrug of 2′,3′-didehydro-2′,3′-dideoxyguanosine (cyclo-d4G) was synthesized, and its cellular metabolism, antiviral activity, and pharmacokinetic behavior were studied. Cyclo-d4G had selective anti-HIV activity in primary blood mononuclear cells (PBMCs), effectively inhibiting the LAI strain of HIV-1 by 50% at 1.1 ± 0.1 μM while showing 50% inhibition of cell viability at 84.5 μM. The antiviral activity in PBMCs was not markedly affected by mutations of methionine to valine at position 184 or by thymidine-associated mutations in the viral reverse transcriptase. Mutations of leucine 74 to valine and of lysine 65 to arginine had mild to moderate resistance (as high as fivefold). Studies to delineate the mechanism of cellular metabolism and activation of cyclo-d4G showed reduced potency in inhibiting viral replication in the presence of the adenosine/adenylate deaminase inhibitor 2′-deoxycoformycin, implying that the antiviral activity is due to its metabolism to the 2′-dGTP analog d4GTP. Intracellular formation of sugar catabolites illustrates the chemical and potentially enzymatic instability of the glycosidic linkage in d4G. Further studies suggest that cyclo-d4G has a novel intracellular phosphorylation pathway. Cyclo-d4G had a lower potential to cause mitochondrial toxicity than 2′,3′-dideoxycytidine and 2′,3′-didehydro-3′-deoxythymidine in neuronal cells. Also, cyclo-d4G had advantageous synergism with many currently used anti-HIV drugs. Poor oral bioavailability observed in rhesus monkeys may be due to the labile glycosidic bond, and special formulation may be necessary for oral delivery.