D- and L-2',3'-didehydro-2',3'-dideoxy-3'-fluoro-carbocyclic nucleosides: synthesis, anti-HIV activity and mechanism of resistance.
D- and L-2',3'-didehydro-2',3'-dideoxy-3'-fluoro-carbocyclic nucleosides: synthesis, anti-HIV activity and mechanism of resistance.
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D-和L-2,3-二脱氢-2,3-二脱氧-3-氟碳环核苷：合成、抗HIV活性和耐药机制。
DOI：
10.1021/jm061304k
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发表时间：
2007
影响因子：
7.3
通讯作者：
Chu,ChungK
中科院分区：
文献类型：
--
作者：
Wang,Jianing;Jin,Yunho;Rapp,KimberlyL;Schinazi,RaymondF;Chu,ChungK
在碳环核苷的2 ‘,3 ’双键上引入2 ' -氟取代，提供了具有有效抗hiv活性的生物学上有趣的化合物。作为我们先前发现抗hiv药物工作的延伸，我们合成了d-和-2 ',3 ' -不饱和3 ' -氟碳环核苷，并在人外周血单核细胞（PBM）中对HIV-1进行了评估。化合物18、19、26和28的抗hiv活性中等（分别为EC507.1 μM、6.4 μM、10.3 μM和20.7 μM），而鸟苷类似物35，d-3′-F-C-d4G的抗hiv活性最高（EC500.4 μM、EC902.8 μM）。然而，鸟苷类似物35对拉米夫定耐药变体（HIV-1M184V）具有交叉耐药。分子模拟研究表明，疏水相互作用和氢键稳定了化合物35在野生型HIV逆转录酶（HIV- rt）活性位点的结合。在非核苷的情况下，这两种作用是相反的，导致结合亲和力的丧失。根据分子模拟研究，d-3′-F-C-d4G（35）对M184V突变体的交叉抗性可能是由于hiv - rtm184v相互作用中引物和模板的重新排列导致rt抑制剂三磷酸复合物不稳定，导致d-鸟嘌呤衍生物的抗hiv活性显著降低35。
Introducing 2‘-fluoro substitution on the 2‘,3‘-double bond in carbocyclic nucleosides has provided biologically interesting compounds with potent anti-HIV activity. As an extension of our previous works in the discovery of anti-HIV agents,d- andl-2‘,3‘-unsaturated 3‘-fluoro carbocyclic nucleosides were synthesized and evaluated against HIV-1 in human peripheral blood mononuclear (PBM) cells. Among the synthesizedl-series nucleosides, compounds18,19,26and28exhibited moderate antiviral activity (EC507.1 μM, 6.4 μM, 10.3 μM, and 20.7 μM, respectively), while among thed-series, the guanosine analogue (35,d-3‘-F-C-d4G) exhibited the most potent anti-HIV activity (EC500.4 μM, EC902.8 μM). However, the guanosine analogue35was cross-resistant to the lamivudine-resistant variants (HIV-1M184V). Molecular modeling studies suggest that hydrophobic interaction as well as hydrogen-bonding stabilize the binding of compound35in the active site of wild type HIV reverse transcriptase (HIV-RT). In the case ofl-nucleosides, these two effects are opposite which results in a loss of binding affinity. According to the molecular modeling studies, cross-resistance ofd-3‘-F-C-d4G (35) to M184V mutant may be caused by the realignment of the primer and template in the HIV-RTM184Vinteraction, which destabilizes the RT-inhibitor triphosphate complex, resulting in a significant reduction in anti-HIV activity of thed-guanine derivative35.
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影响因子：
7.3
作者：
Jianing Wang;Yunho Jin;K. Rapp;M. Bennett;R. Schinazi;C. K. Chu
通讯作者：
Jianing Wang;Yunho Jin;K. Rapp;M. Bennett;R. Schinazi;C. K. Chu
司他夫定在人类免疫缺陷病毒感染患者中的剂量相关活性。
影响因子：
6.4
作者：
Eskild A. Petersen;C. H. Ramírez;W. Hardy;Robert Schwartz;Henry S. Sacks;Stephen E. Follansbee;Dolores M. Peterson;Anne H. Cross;Robert E. Anderson;Lisa M. Dunkle
通讯作者：
Lisa M. Dunkle
深入了解三磷酸卡波韦对 HIV-1 RT 的抑制和耐药性的分子机制。
影响因子：
2.9
作者：
Ray,AdrianS;Yang,Zhenjun;Shi,Junxing;Hobbs,Ann;Schinazi,RaymondF;Chu,ChungK;Anderson,KarenS
通讯作者：
Anderson,KarenS
影响因子：
7.3
作者：
Wen Zhou;G. Gumina;Youhoon Chong;Jianing Wang;R. Schinazi;C. K. Chu
通讯作者：
Wen Zhou;G. Gumina;Youhoon Chong;Jianing Wang;R. Schinazi;C. K. Chu
早期检测抗逆转录病毒药物在感染艾滋病毒的原代人淋巴细胞中选择的混合突变。
DOI：
--
发表时间：
2001
期刊：
Antiviral chemistry & chemotherapy.
影响因子：
--
作者：
Schinazi,RF;Schlueter-Wirtz,S;Stuyver,L
通讯作者：
Stuyver,L