Potential Tools for Eradicating HIV Reservoirs in the Brain: Development of Trojan Horse Prodrugs for the Inhibition of P‑Glycoprotein with Anti-HIV‑1 Activity

Combination
antiretroviral therapy is the mainstay of HIV treatment,
lowering plasma viral levels below detection. However, eradication
of HIV is a major challenge due to cellular and anatomical viral reservoirs
that are often protected from treatment by efflux transporters, such
as P-glycoprotein (P-gp) at the blood–brain barrier (BBB).
Herein we described a Trojan horse approach to therapeutic evasion
of P-gp based on a reversibly linked combination of HIV reverse transcriptase
and protease inhibitors. Potent inhibition of P-gp efflux in cells,
including human brain endothelial cells, was observed with the linked
heterodimeric compounds. In vitro regeneration of active monomeric
drugs was observed in a reducing environment with these dimeric prodrugs,
with the superior leaving group promoting more facile release from
the tether. These release trends were mirrored in the efficacy of
the in cyto anti-HIV-1 activity of the Trojan horse heterodimers.