Inhibition of Tat-mediated HIV-1 replication and neurotoxicity by novel GSK3-beta inhibitors

Kylene Kehn-Hall; Irene Guendel; Lawrence Carpio; Leandros Skaltsounis; Laurent Meijer; Lena Al-Harthi; Joseph P. Steiner; Avindra Nath; Olaf Kutsch; Fatah Kashanchi

doi:10.1016/j.virol.2011.03.025

Inhibition of Tat-mediated HIV-1 replication and neurotoxicity by novel GSK3-beta inhibitors

Kylene Kehn-Hall, Irene Guendel, Lawrence Carpio, Leandros Skaltsounis, Laurent Meijer, Lena Al-Harthi, Joseph P. Steiner, Avindra Nath, Olaf Kutsch, Fatah Kashanchi

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

Abstract

The HIV-1 protein Tat is a critical regulator of viral transcription and has also been implicated as a mediator of HIV-1 induced neurotoxicity. Here using a high throughput screening assay, we identified the GSK-3 inhibitor 6BIO, as a Tat-dependent HIV-1 transcriptional inhibitor. Its ability to inhibit HIV-1 transcription was confirmed in TZM-bl cells, with an IC₅₀ of 40nM. Through screening 6BIO derivatives, we identified 6BIOder, which has a lower IC₅₀ of 4nM in primary macrophages and 0.5nM in astrocytes infected with HIV-1. 6BIOder displayed an IC₅₀ value of 0.03nM through in vitro GSK-3β kinase inhibition assays. Finally, we demonstrated 6BIO and 6BIOder have neuroprotective effects on Tat induced cell death in rat mixed hippocampal cultures. Therefore 6BIO and its derivatives are unique compounds which, due to their complex mechanisms of action, are able to inhibit HIV-1 transcription as well as to protect against Tat induced neurotoxicity.

Original language	English (US)
Pages (from-to)	56-68
Number of pages	13
Journal	Virology
Volume	415
Issue number	1
DOIs	https://doi.org/10.1016/j.virol.2011.03.025
State	Published - Jun 20 2011
Externally published	Yes

Keywords

GSK-3
HAND
HIV-1
Indirubin
Neuroprotection
Tat
Therapeutic target
Transcriptional inhibition

ASJC Scopus subject areas

Virology

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10.1016/j.virol.2011.03.025

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title = "Inhibition of Tat-mediated HIV-1 replication and neurotoxicity by novel GSK3-beta inhibitors",

abstract = "The HIV-1 protein Tat is a critical regulator of viral transcription and has also been implicated as a mediator of HIV-1 induced neurotoxicity. Here using a high throughput screening assay, we identified the GSK-3 inhibitor 6BIO, as a Tat-dependent HIV-1 transcriptional inhibitor. Its ability to inhibit HIV-1 transcription was confirmed in TZM-bl cells, with an IC50 of 40nM. Through screening 6BIO derivatives, we identified 6BIOder, which has a lower IC50 of 4nM in primary macrophages and 0.5nM in astrocytes infected with HIV-1. 6BIOder displayed an IC50 value of 0.03nM through in vitro GSK-3β kinase inhibition assays. Finally, we demonstrated 6BIO and 6BIOder have neuroprotective effects on Tat induced cell death in rat mixed hippocampal cultures. Therefore 6BIO and its derivatives are unique compounds which, due to their complex mechanisms of action, are able to inhibit HIV-1 transcription as well as to protect against Tat induced neurotoxicity.",

keywords = "GSK-3, HAND, HIV-1, Indirubin, Neuroprotection, Tat, Therapeutic target, Transcriptional inhibition",

author = "Kylene Kehn-Hall and Irene Guendel and Lawrence Carpio and Leandros Skaltsounis and Laurent Meijer and Lena Al-Harthi and Steiner, {Joseph P.} and Avindra Nath and Olaf Kutsch and Fatah Kashanchi",

note = "Funding Information: We would like to thank Ben Berkhout for the Dox Tat/TAR viruses. This work was supported by NIH grants AI0078859 , AI0074410 and NS070740 to Fatah Kashanchi and NIH grant NS060632 to Lena Al-Harthi. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.",

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AU - Kehn-Hall, Kylene

AU - Guendel, Irene

AU - Carpio, Lawrence

AU - Skaltsounis, Leandros

AU - Meijer, Laurent

AU - Al-Harthi, Lena

AU - Steiner, Joseph P.

AU - Nath, Avindra

AU - Kutsch, Olaf

AU - Kashanchi, Fatah

N1 - Funding Information: We would like to thank Ben Berkhout for the Dox Tat/TAR viruses. This work was supported by NIH grants AI0078859 , AI0074410 and NS070740 to Fatah Kashanchi and NIH grant NS060632 to Lena Al-Harthi. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

PY - 2011/6/20

Y1 - 2011/6/20

N2 - The HIV-1 protein Tat is a critical regulator of viral transcription and has also been implicated as a mediator of HIV-1 induced neurotoxicity. Here using a high throughput screening assay, we identified the GSK-3 inhibitor 6BIO, as a Tat-dependent HIV-1 transcriptional inhibitor. Its ability to inhibit HIV-1 transcription was confirmed in TZM-bl cells, with an IC50 of 40nM. Through screening 6BIO derivatives, we identified 6BIOder, which has a lower IC50 of 4nM in primary macrophages and 0.5nM in astrocytes infected with HIV-1. 6BIOder displayed an IC50 value of 0.03nM through in vitro GSK-3β kinase inhibition assays. Finally, we demonstrated 6BIO and 6BIOder have neuroprotective effects on Tat induced cell death in rat mixed hippocampal cultures. Therefore 6BIO and its derivatives are unique compounds which, due to their complex mechanisms of action, are able to inhibit HIV-1 transcription as well as to protect against Tat induced neurotoxicity.

AB - The HIV-1 protein Tat is a critical regulator of viral transcription and has also been implicated as a mediator of HIV-1 induced neurotoxicity. Here using a high throughput screening assay, we identified the GSK-3 inhibitor 6BIO, as a Tat-dependent HIV-1 transcriptional inhibitor. Its ability to inhibit HIV-1 transcription was confirmed in TZM-bl cells, with an IC50 of 40nM. Through screening 6BIO derivatives, we identified 6BIOder, which has a lower IC50 of 4nM in primary macrophages and 0.5nM in astrocytes infected with HIV-1. 6BIOder displayed an IC50 value of 0.03nM through in vitro GSK-3β kinase inhibition assays. Finally, we demonstrated 6BIO and 6BIOder have neuroprotective effects on Tat induced cell death in rat mixed hippocampal cultures. Therefore 6BIO and its derivatives are unique compounds which, due to their complex mechanisms of action, are able to inhibit HIV-1 transcription as well as to protect against Tat induced neurotoxicity.

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KW - Therapeutic target

KW - Transcriptional inhibition

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Inhibition of Tat-mediated HIV-1 replication and neurotoxicity by novel GSK3-beta inhibitors

Abstract

Keywords

ASJC Scopus subject areas

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