Toward eradicating HIV reservoirs in the brain: inhibiting P-glycoprotein at the blood-brain barrier with prodrug abacavir dimers.
Toward eradicating HIV reservoirs in the brain: inhibiting P-glycoprotein at the blood-brain barrier with prodrug abacavir dimers.
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DOI：
10.1021/ja206867t
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发表时间：
2012-02-15
影响因子：
15
通讯作者：
Chmielewski, Jean
中科院分区：
文献类型：
--
作者：
Namanja, Hilda A.;Emmert, Dana;Davis, David A.;Campos, Christopher;Miller, David S.;Hrycyna, Christine A.;Chmielewski, Jean
消除脑中的HIV储库需要抗病毒剂穿过血脑屏障（BBB），这是一个受药物外排蛋白如脑毛细血管内皮细胞膜处的P-糖蛋白（P-gp）限制的过程。我们提出了一种创新的化学策略，其目标是将P-gp底物和抗病毒药物阿巴卡韦与无痕系链一起用于治疗性脑渗透。阿巴卡韦的二聚体前药被设计为具有两种功能：抑制BBB处的P-gp流出和在细胞还原环境内恢复为单体治疗剂。前药二聚体是细胞培养物和BBB脑毛细血管模型中的有效P-gp抑制剂。值得注意的是，这些药物在两种基于T细胞的HIV检测中显示出抗HIV活性，这一结果与前药向阿巴卡韦的细胞逆转有关。该策略代表了一种平台技术，可应用于由于P-糖蛋白而导致脑渗透有限的其他疗法。
Eradication of HIV reservoirs in the brain necessitates penetration of antiviral agents across the blood-brain barrier (BBB), a process limited by drug efflux proteins such as P-glycoprotein (P-gp) at the membrane of brain capillary endothelial cells. We present an innovative chemical strategy toward the goal of therapeutic brain penetration of the P-gp substrate and anti-viral agent abacavir, in conjunction with a traceless tether. Dimeric prodrugs of abacavir were designed to have two functions: inhibit P-gp efflux at the BBB and revert to monomeric therapeutic within cellular reducing environments. The prodrug dimers are potent P-gp inhibitors in cell culture and in a brain capillary model of the BBB. Significantly, these agents demonstrate anti-HIV activity in two T-cell-based HIV assays, a result that is linked to cellular reversion of the prodrug to abacavir. This strategy represents a platform technology that may be applied to other therapies with limited brain penetration due to P-glycoprotein.
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影响因子：
2.7
作者：
Henne, Walter A.;Doorneweerd, Derek D.;Low, Philip S.
通讯作者：
Low, Philip S.
DOI：
10.1073/pnas.93.24.14164
发表时间：
1996-11-26
影响因子：
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作者：
Huwyler, J;Wu, DF;Pardridge, WM
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Pardridge, WM
评估高效抗逆转录病毒疗法在大脑中的疗效
影响因子：
6.4
作者：
Kandanearatchi, A;Williams, B;Everall, IP
通讯作者：
Everall, IP
DOI：
10.1126/science.1168750
发表时间：
2009-03-27
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
Aller SG;Yu J;Ward A;Weng Y;Chittaboina S;Zhuo R;Harrell PM;Trinh YT;Zhang Q;Urbatsch IL;Chang G
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Chang G
DOI：
10.1073/pnas.94.20.10594
发表时间：
1997-09-30
影响因子：
11.1
作者：
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通讯作者：
Ambudkar, SV