Novel neuroprotective GSK-3β inhibitor restricts Tat-mediated HIV-1 replication.
The implementation of new antiretroviral therapies targeting transcription of early viral proteins in postintegrated HIV-1 can aid in overcoming current therapy limitations. Using high-throughput screening assays, we have previously described a novel Tat-dependent HIV-1 transcriptional inhibitor named 6-bromoindirubin-3'-oxime (6BIO). The screening of 6BIO derivatives yielded unique compounds that show potent inhibition of HIV-1 transcription. We have identified a second-generation derivative called 18BIOder as an inhibitor of HIV-1 Tat-dependent transcription in TZM-bl cells and a potent inhibitor of GSK-3β kinase in vitro. Structurally, 18BIOder is half the molecular weight and structure of its parental compound, 6BIO. More importantly, we also have found a different GSK-3β complex present only in HIV-1-infected cells. 18BIOder preferentially inhibits this novel kinase complex from infected cells at nanomolar concentrations. Finally, we observed that neuronal cultures treated with Tat protein are protected from Tat-mediated cytotoxicity when treated with 18BIOder. Overall, our data suggest that HIV-1 Tat-dependent transcription is sensitive to small-molecule inhibition of GSK-3β.
National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, Virginia, USA.
Irene
I
Guendel
Sergey
S
Iordanskiy
Rachel
R
Van Duyne
Kylene
K
Kehn-Hall
Mohammed
M
Saifuddin
Ravi
R
Das
Elizabeth
E
Jaworski
Gavin C
GC
Sampey
Svetlana
S
Senina
Leonard
L
Shultz
Aarthi
A
Narayanan
Hao
H
Chen
Benjamin
B
Lepene
Chen
C
Zeng
Fatah
F
Kashanchi
D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D015658:HIV Infections / Q000188:drug therapy / Q000201:enzymology / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D009474:Neurons / Q000821:virology*; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
C483321:6-bromoindirubin-3'-oxime; D019380:Anti-HIV Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D018696:Neuroprotective Agents; D010091:Oximes; D054322:tat Gene Products, Human Immunodeficiency Virus; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3