Tools for Eradicating HIV Reservoirs in the Brain: A Trojan Horse Approach

根除大脑中艾滋病毒储存库的工具：特洛伊木马方法

• 批准号: 8544598
• 负责人: JEAN A CHMIELEWSKI
• 金额: $ 20.32万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8544598
• 关键词: ATP-Binding Cassette Transporters; Affect; Affinity; Anti-Retroviral Agents; Antiviral Agents; Atazanavir; Binding; Biological Assay; Blood - brain barrier anatomy; Blood capillaries; Brain; Capillary Endothelial Cell; Cell Culture Techniques; Cells; Culture Media; Cytosol; Development; Endothelial Cells; Environment; Equus caballus; Focus Groups; Funding; Goals; HIV; Human; In Situ; Lamivudine; Measures; Microglia; Modeling; Monitor; Natural regeneration; Nelfinavir; Penetration; Perfusion; Pharmaceutical Preparations; Plasma; Rattus; Saquinavir; Site; Testing; Therapeutic Agents; Work; abacavir; antiretroviral therapy; base; capillary; dimer; improved; inhibitor/antagonist; public health relevance; tool

DESCRIPTION (provided by applicant): Despite positive developments with the use of combination antiretroviral therapy, a major impediment to eradicating brain reservoirs is penetration of these therapies across the blood- brain-barrier. The focus of this proposal, therefore, is to develop tools to significantly improve the penetration of antiretroviral agents to sites of HIV reservoirs with an emphasis on the brain. To this end, we propose the use of a new class of agents - Trojan Horse dimers of known ART to evade P-gp at the BBB and deliver antiretroviral therapies to the brain. ART that are known to be P-gp substrates will be dimerized, as work from our labs has demonstrated that dimers of P-gp substrates can be readily converted into potent P-gp inhibitors. These Trojan Horse (TH) dimers will serve two purposes: (1) they will evade P-gp efflux, enter the endothelial cells at the BBB and revert to active ART in the reducing environment of the cytosol, and (2) they will inhibit P-gp at the BBB thus boosting the brain levels of other ART that are substrates of P-gp. We hypothesize that both administration of TH dimers alone, and co-administration with monomeric drugs, would serve to increase the level of the therapeutic agents in the brain.

描述（由申请人提供）：尽管联合抗逆转录病毒疗法的使用取得了积极进展，但根除脑储存库的主要障碍是这些疗法穿过血脑屏障的渗透。因此，该提案的重点是开发工具来显着提高抗逆转录病毒药物的渗透性 HIV 储存库的部位，重点是大脑。 为此，我们建议使用一类新的药物——已知 ART 的特洛伊木马二聚体来逃避 BBB 处的 P-gp 并向大脑提供抗逆转录病毒治疗。已知为 P-gp 底物的 ART 将被二聚化，因为我们实验室的工作已经证明 P-gp 底物的二聚体可以很容易地转化为有效的 P-gp 抑制剂。这些特洛伊木马 (TH) 二聚体将有两个目的：(1) 它们将逃避 P-gp 外流，进入 BBB 处的内皮细胞，并在 (2) 它们会抑制 BBB 处的 P-gp，从而提高作为 P-gp 底物的其他 ART 的大脑水平。我们假设单独施用 TH 二聚体以及与单体药物共同施用都将有助于增加大脑中治疗药物的水平。