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.
At the completion of the proposed funding period, we will have Trojan Horse dimers that are not only potent P-gp inhibitors at the BBB, but also display cellular antiretroviral activity. Although this proposal targets P-gp inhibition at the BBB with a focused group of compounds, in the long-term our studies will be expanded to include other ART and other ABC transporters. We have focused in this proposal specifically on P-gp at the BBB, but our approach also has the potential to concomitantly affect other cellular and anatomical reservoirs of HIV where P-gp is expressed.
|Namanja, Hilda A; Emmert, Dana; Hrycyna, Christine A et al. (2013) Homodimers of the Antiviral Abacavir as Modulators of P-glycoprotein Transport in Cell Culture: Probing Tether Length. Medchemcomm 4:|