Homodimers of the antiviral abacavir as modulators of P-glycoprotein transport in cell culture

Probing tether length

Hilda A. Namanja, Dana Emmert, Christine A. Hrycyna, Jean Chmielewski

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

A major hurdle in permanently eliminating HIV from the body is the persistence of viral reservoirs, including those of the brain. One potential strategy towards eradicating HIV reservoirs of the brain is to block efflux transporters, such as P-glycoprotein (P-gp), that contribute to the limited penetration of antiviral agents across the blood-brain barrier (BBB). Herein, we described a series of dimeric inhibitors of P-gp based on the nucleoside reverse transcriptase inhibitor and P-gp substrate, abacavir. Varying tether lengths were used to generate abacavir dimers to probe tether requirements for inhibitory potency. These dimeric agents were evaluated in two cell lines that express P-gp at varying levels: a P-gp over-expressing CD4+ T-lymphocyte cell line (12D7-MDR) and a human brain capillary endothelial cell line as an in vitro model of the BBB (hCMEC/D3) that expresses endogenous levels of P-gp. All dimeric abacavir analogs were inhibitors of P-gp efflux in the two cell lines with potencies that varied with tether length; the most potent agents displayed low micromolar inhibition. P-gp inhibition in a highly P-gp over-expressing cell line (MCF-7/DX1) was also observed with a range of therapeutic substrates. Competition studies with the photoaffinity substrate [125I]iodoarylazidoprazosin demonstrated that abacavir dimers act by competing for the substrate binding sites of P-gp. These data demonstrate that the tether length of dimeric abacavir derivatives has a significant effect on inhibition of P-gp drug efflux, with up to a 35-fold increase in potency observed with longer tether linkages.

Original languageEnglish (US)
Pages (from-to)1344-1349
Number of pages6
JournalMedChemComm
Volume4
Issue number10
DOIs
StatePublished - Oct 2013
Externally publishedYes

Fingerprint

P-Glycoprotein
Cell culture
Modulators
Antiviral Agents
Cell Culture Techniques
Cell Line
Cells
Brain
Substrates
Blood-Brain Barrier
Dimers
abacavir
HIV
Reverse Transcriptase Inhibitors
T-cells
Endothelial cells
Nucleosides
Endothelial Cells
Binding Sites
Derivatives

ASJC Scopus subject areas

  • Biochemistry
  • Pharmaceutical Science

Cite this

Homodimers of the antiviral abacavir as modulators of P-glycoprotein transport in cell culture : Probing tether length. / Namanja, Hilda A.; Emmert, Dana; Hrycyna, Christine A.; Chmielewski, Jean.

In: MedChemComm, Vol. 4, No. 10, 10.2013, p. 1344-1349.

Research output: Contribution to journalArticle

Namanja, Hilda A. ; Emmert, Dana ; Hrycyna, Christine A. ; Chmielewski, Jean. / Homodimers of the antiviral abacavir as modulators of P-glycoprotein transport in cell culture : Probing tether length. In: MedChemComm. 2013 ; Vol. 4, No. 10. pp. 1344-1349.
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