Journal article
Novel Neuroprotective GSK-3β Inhibitor Restricts Tat-Mediated HIV-1 Replication
Journal of virology, v 88(2), pp 1189-1208
01 Jan 2014
PMID: 24227837
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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Details
- Title
- Novel Neuroprotective GSK-3β Inhibitor Restricts Tat-Mediated HIV-1 Replication
- Creators
- Irene Guendel - George Mason UniversitySergey Iordanskiy - George Mason UniversityRachel Van Duyne - George Mason UniversityKylene Kehn-Hall - George Mason UniversityMohammed Saifuddin - George Mason UniversityRavi Das - George Mason UniversityElizabeth Jaworski - George Mason UniversityGavin C. Sampey - George Mason UniversitySvetlana Senina - George Mason UniversityLeonard Shultz - Jackson LaboratoryAarthi Narayanan - George Mason UniversityHao Chen - George Washington UniversityBenjamin Lepene - Ceres NanosciencesChen Zeng - Huazhong University of Science and TechnologyFatah Kashanchi - George Mason University
- Publication Details
- Journal of virology, v 88(2), pp 1189-1208
- Publisher
- American Society for Microbiology
- Number of pages
- 20
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000329194900039
- Scopus ID
- 2-s2.0-84891701581
- Other Identifier
- 991021902532004721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Virology