Toward Eradicating HIV Reservoirs in the Brain: Inhibiting P-Glycoprotein at the Blood鈥揃rain Barrier with Prodrug Abacavir Dimers

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• 作者：Hilda A. Namanja ; Dana Emmert ; David A. Davis ; Christopher Campos ; David S. Miller ; Christine A. Hrycyna ; Jean Chmielewski
• 刊名：The Journal of the American Chemical Society
• 出版年：2012
• 出版时间：February 15, 2012
• 年：2012
• 卷：134
• 期：6
• 页码：2976-2980
• 全文大小：804K
• 年卷期：v.134,no.6(February 15, 2012)
• ISSN：1520-5126

文摘

Eradication of HIV reservoirs in the brain necessitates penetration of antiviral agents across the blood鈥揵rain 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 antiviral 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.