Development of dimeric prodrug inhibitors of P-glycoprotein and ABCG2 to enhance brain penetration of antiretroviral agents

Hilda Andamiche Namanja, Purdue University

Abstract

A major obstacle in eradicating the human immunodeficiency virus type 1 (HIV-1) is the development of viral reservoirs in the host's cells and several anatomical organs including the brain. Brain reservoirs result from limited penetration of anti-retroviral therapeutics caused in part by efflux transporters such as P-glycoprotein (P-gp) and ABCG2 at the blood-brain barrier (BBB). Thus the development of inhibitors of P-gp and ABCG2 is a promising strategy for increasing drug penetration in order to eradicate the HIV reservoirs. We have developed two classes of dimeric prodrug inhibitors based on HIV-1 protease inhibitors (HIV-PIs) and the nucleoside reverse transcriptase inhibitors (NRTIs), abacavir and zidovudine (AZT). The first class consisted of homodimeric inhibitors of P-gp and ABCG2 which were designed to have two functions: (a) inhibit efflux by P-gp/and or ABCG2 at the BBB and (b) revert to monomer within cellular environments for HIV therapy. Many of these homodimers were found to inhibit the transporters in cell culture. Competition studies with the substrate [125I] iodoarylazidoprazosin showed that these dimers inhibit by competing with substrates for binding sites on P-gp and BCG2. Further studies with abacavir prodrug homodimers demonstrated that these compounds are potent inhibitors of P-gp in T –lymphocytes, brain endothelial cells and rat brain capillaries. In addition, the abacavir dimers inhibited HIV-1 replication in MT-2 and 12D7 T-cells due to reversion of the dimers to therapeutic abacavir in cellular reducing conditions. The second class of compounds were heterodimeric inhibitors composed of an HIV-PI and a NRTI linked by a tether. These heterodimers would function to inhibit P-gp and ABCG2, and also revert to monomers within cellular environments for combination HIV therapy. Heterodimers based on the HIV-PIs amprenavir, saquinavir and ritonavir and the NRTIs abacavir and AZT were synthesized and found to inhibit P-gp and ABCG2 in mammalian cells.

Degree

Ph.D.

Advisors

Chmielewski, Purdue University.

Subject Area

Chemistry|Biochemistry|Pharmacy sciences

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