Chmielewski Jean, Hrycyna Christine
Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.
Ther Deliv. 2012 Jun;3(6):689-92. doi: 10.4155/tde.12.49.
Despite positive developments with the use of combination antiretroviral therapy, a major impediment to limiting the neurocognitive effects of HIV and eradicating HIV brain reservoirs is the penetration of these therapies across the blood-brain barrier (BBB). The focus of our work, therefore, has been to develop tools to significantly improve the penetration of antiretroviral agents to sites of HIV reservoirs, with an emphasis on the CNS. To this end, we have developed an innovative chemical approach--dimeric prodrugs of the antiretroviral agents themselves with a traceless tether. These dimeric prodrugs were designed to serve two purposes: inhibition of P-gp, the major drug efflux protein at the BBB, by occupying two substrate binding sites in the transporter; and prodrug dimers that gain entry into the endothelial cells at the BBB would revert to their monomeric forms in the reducing environment of the cytosol due to breakdown of the traceless tether, thus delivering the therapy. We have demonstrated the feasibility of this design by dimerizing the P-gp substrate and antiviral agent abacavir with a traceless tether. Abacavir dimers displayed potent inhibition of P-gp in two different cellular settings and reverted to active abacavir in the reducing environment of HIV-infected T cells, also leading to antiviral activity. Overall, these experiments point to the excellent promise for future use of dimeric prodrug inhibitors of P-gp for brain penetration of a wide range of CNS-active agents that are substrates of P-gp.
尽管联合抗逆转录病毒疗法取得了积极进展，但限制HIV神经认知效应和根除HIV脑内储存库的一个主要障碍是这些疗法穿过血脑屏障（BBB）的能力。因此，我们工作的重点是开发工具，以显著提高抗逆转录病毒药物进入HIV储存库部位的渗透率，重点是中枢神经系统（CNS）。为此，我们开发了一种创新的化学方法——使用无痕连接子将抗逆转录病毒药物本身制成二聚体前药。这些二聚体前药旨在实现两个目的：通过占据转运蛋白中的两个底物结合位点来抑制P-糖蛋白（BBB处主要的药物外排蛋白）；进入BBB处内皮细胞的前药二聚体，由于无痕连接子的断裂，会在细胞质的还原环境中恢复为单体形式，从而实现治疗效果。我们通过使用无痕连接子将P-糖蛋白底物和抗病毒药物阿巴卡韦二聚化，证明了这种设计的可行性。阿巴卡韦二聚体在两种不同的细胞环境中均显示出对P-糖蛋白的有效抑制作用，并在HIV感染的T细胞的还原环境中恢复为活性阿巴卡韦，同时也产生了抗病毒活性。总体而言，这些实验表明，P-糖蛋白二聚体前药抑制剂在未来用于多种作为P-糖蛋白底物的中枢神经系统活性药物的脑内渗透方面具有极好的前景。
