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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

[Image: see text] 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 a...

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Autores principales: Agrawal, Neha, Rowe, Jennifer, Lan, Jie, Yu, Qigui, Hrycyna, Christine A., Chmielewski, Jean
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2019
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073916/
https://www.ncbi.nlm.nih.gov/pubmed/31505928
http://dx.doi.org/10.1021/acs.jmedchem.9b00779
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author Agrawal, Neha
Rowe, Jennifer
Lan, Jie
Yu, Qigui
Hrycyna, Christine A.
Chmielewski, Jean
author_facet Agrawal, Neha
Rowe, Jennifer
Lan, Jie
Yu, Qigui
Hrycyna, Christine A.
Chmielewski, Jean
author_sort Agrawal, Neha
collection PubMed
description [Image: see text] 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.
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spelling pubmed-70739162020-03-17 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 Agrawal, Neha Rowe, Jennifer Lan, Jie Yu, Qigui Hrycyna, Christine A. Chmielewski, Jean J Med Chem [Image: see text] 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. American Chemical Society 2019-09-11 2020-03-12 /pmc/articles/PMC7073916/ /pubmed/31505928 http://dx.doi.org/10.1021/acs.jmedchem.9b00779 Text en Copyright © 2019 American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
spellingShingle Agrawal, Neha
Rowe, Jennifer
Lan, Jie
Yu, Qigui
Hrycyna, Christine A.
Chmielewski, Jean
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073916/
https://www.ncbi.nlm.nih.gov/pubmed/31505928
http://dx.doi.org/10.1021/acs.jmedchem.9b00779
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