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

Neha Agrawal, Jennifer Rowe, Jie Lan, Qigui Yu, Christine A. Hrycyna, Jean Chmielewski

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2131-2138
Number of pages8
JournalJournal of Medicinal Chemistry
Volume63
Issue number5
DOIs
StatePublished - Mar 12 2020

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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