Novel neuroprotective GSK-3β inhibitor restricts Tat-mediated HIV-1 replication.

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Journal of virology, ISSN: 1098-5514, Vol: 88, Issue: 2, Page: 1189-208

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Guendel, Irene; Iordanskiy, Sergey N.; Van Duyne, Rachel; Kehn-Hall, Kylene; Saifuddin, Mohammed; Das, Ravi; Jaworski, Elizabeth; Sampey, Gavin C.; Senina, Svetlana; Shultz, Leonard; Narayanan, Aarthi; Hao, Chen; Lepene, Benjamin; Zeng, Chen; Kashanchi, Fatah Show More Hide
American Society for Microbiology; American Society For Microbiology
Immunology and Microbiology; Anti-HIV Agents; Enzyme Inhibitors; Glycogen Synthase Kinase 3; HIV Infections; HIV-1; Humans; Indoles; Neurons; Neuroprotective Agents; Oximes; Transcription; Genetic; Virus Replication; tat Gene Products; Human Immunodeficiency Virus; Medical Immunology; Medical Microbiology; Life Sciences; Medicine and Health Sciences
article description
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.