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 journalArticlepeer-review

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 languageEnglish (US)
Pages (from-to)56-68
Number of pages13
JournalVirology
Volume415
Issue number1
DOIs
StatePublished - Jun 20 2011

Keywords

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

ASJC Scopus subject areas

  • Virology

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