Document Type
Journal Article
Publication Date
1-2014
Journal
Journal of Virology
Volume
Volume 88, Issue 2
Inclusive Pages
1189-1208
Abstract
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.
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License.
APA Citation
Guendel, I., Iordanskiy, S., Van Duyne, R., Kehn-Hall, K., Saifuddin, M. et al. (2014). Novel neuroprotective GSK-3β inhibitor restricts tat-mediated HIV-1 replication. Journal of Virology, 88(2), 1189-1208.
Peer Reviewed
1
Open Access
1
Comments
Copyright © American Society for Microbiology, Journal of Virology, 88(2), 2014, 1189; DOI: 10.1128/JVI.01940-13.