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 IC(50) of 40nM. Through screening 6BIO derivatives, we identified 6BIOder, which has a lower IC(50) of 4nM in primary macrophages and 0.5nM in astrocytes infected with HIV-1. 6BIOder displayed an IC(50) 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.
authors.affiliation: Department of Molecular and Microbiology, National Center for Biodefense & Infectious Diseases, George Mason University, Manassas, VA 20110, USA.
authors.forename: Kylene
authors.initials: K
authors.lastname: Kehn-Hall
authors.forename: Irene
authors.initials: I
authors.lastname: Guendel
authors.forename: Lawrence
authors.initials: L
authors.lastname: Carpio
authors.forename: Leandros
authors.initials: L
authors.lastname: Skaltsounis
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.forename: Lena
authors.initials: L
authors.lastname: Al-Harthi
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Steiner
authors.forename: Avindra
authors.initials: A
authors.lastname: Nath
authors.forename: Olaf
authors.initials: O
authors.lastname: Kutsch
authors.forename: Fatah
authors.initials: F
authors.lastname: Kashanchi
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D001253:Astrocytes / Q000378:metabolism / Q000821:virology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D015870:Gene Expression / Q000187:drug effects; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D057166:High-Throughput Screening Assays; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism / Q000821:virology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000633:toxicity; D010091:Oximes / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism* / Q000633:toxicity*
chemical_list: C483321:6-bromoindirubin-3'-oxime; D019380:Anti-HIV Agents; D007211:Indoles; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010091:Oximes; D054322:tat Gene Products, Human Immunodeficiency Virus; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3