Novel neuroprotective GSK-3β inhibitor restricts Tat-mediated HIV-1 replication.
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
J Virol 2014 Jan; 88(2):1189-1208.
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. J Virol 2014 Jan; 88(2):1189-1208.
Guendel, Irene; Iordanskiy, Sergey; Van Duyne, Rachel; Kehn-Hall, Kylene; Saifuddin, Mohammed; Das, Ravi; Jaworski, Elizabeth; Sampey, Gavin C; Senina, Svetlana; Shultz, Leonard D.; Narayanan, Aarthi; Chen, Hao; Lepene, Benjamin; Zeng, Chen; and Kashanchi, Fatah, "Novel neuroprotective GSK-3β inhibitor restricts Tat-mediated HIV-1 replication." (2014). Faculty Research 2014. 49.