Novel Neuroprotective GSK-3β Inhibitor Restricts Tat-Mediated HIV-1 Replication
Novel Neuroprotective GSK-3β Inhibitor Restricts Tat-Mediated HIV-1 Replication
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DOI：
10.1128/jvi.01940-13
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发表时间：
2014-01-01
影响因子：
5.4
通讯作者：
Kashanchi, Fatah
中科院分区：
文献类型：
--
作者：
Guendel, Irene;Iordanskiy, Sergey;Kashanchi, Fatah
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-3 beta 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-3 beta 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 Tatdependent transcription is sensitive to small-molecule inhibition of GSK-3 beta.
