title: Toward eradicating HIV reservoirs in the brain: inhibiting P-glycoprotein at the blood-brain barrier with prodrug abacavir dimers.
abstract: 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 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.
authors.affiliation: Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907-2084, USA.
authors.forename: Hilda A
authors.initials: HA
authors.lastname: Namanja
authors.forename: Dana
authors.initials: D
authors.lastname: Emmert
authors.forename: David A
authors.initials: DA
authors.lastname: Davis
authors.forename: Christopher
authors.initials: C
authors.lastname: Campos
authors.forename: David S
authors.initials: DS
authors.lastname: Miller
authors.forename: Christine A
authors.initials: CA
authors.lastname: Hrycyna
authors.forename: Jean
authors.initials: J
authors.lastname: Chmielewski
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000255:Adenosine Triphosphate / Q000737:chemistry; D019380:Anti-HIV Agents / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000821:virology; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015224:Dideoxynucleosides / Q000494:pharmacology*; D019281:Dimerization; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D011355:Prodrugs / Q000494:pharmacology*; D000099227:Abacavir
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000255:Adenosine Triphosphate; D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D011355:Prodrugs; D000099227:Abacavir