Abstract
HIV-1 Associated Neurocognitive Disorder (HAND) is a common and clinically detrimental complication of HIV infection. Viral proteins, including Tat, released from infected cells, cause neuronal toxicity. Substance abuse in HIV-infected patients greatly influences the severity of neuronal damage. To repurpose small molecule inhibitors for anti-HAND therapy, we employed MOLIERE, an AI-based literature mining system that we developed. All human genes were analyzed and prioritized by MOLIERE to find previously unknown targets connected to HAND. From the identified high priority genes, we narrowed the list to those with known small molecule ligands developed for other applications and lacking systemic toxicity in animal models. To validate the AI-based process, the selective small molecule inhibitor of DDX3 helicase activity, RK-33, was chosen and tested for neuroprotective activity. The compound, previously developed for cancer treatment, was tested for the prevention of combined neurotoxicity of HIV Tat and cocaine. Rodent cortical cultures were treated with 6 or 60 ng/ml of HIV Tat and 10 or 25 μM of cocaine, which caused substantial toxicity. RK-33 at doses as low as 1 μM greatly reduced the neurotoxicity of Tat and cocaine. Transcriptome analysis showed that most Tat-activated transcripts are microglia-specific genes and that RK-33 blocks their activation. Treatment with RK-33 inhibits the Tat and cocaine-dependent increase in the number and size of microglia and the proinflammatory cytokines IL-6, TNF-α, MCP-1/CCL2, MIP-2, IL-1α and IL-1β. These findings reveal that inhibition of DDX3 may have the potential to treat not only HAND but other neurodegenerative diseases.
RK-33, selective inhibitor of Dead Box RNA helicase 3 (DDX3) protects neurons from combined Tat and cocaine neurotoxicity by inhibition of microglia activation and production of proinflammatory cytokines.
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Acknowledgments
We thank Dr. Amar N. Kar for the help with primary cortical cultures, Drs. Jeffery L. Twiss, Anna Kashina, Pavel Ortinski and Inna Grosheva for fruitful discussions and critical reading of the manuscript. We thank the cores of COBRE Center for Targeted Therapeutics for transcriptomics analysis (Functional Genomics Core) and microscopy and image analysis (Microscopy and Flow cytometry Core). We thank Drs Chinenov and Oliver (The David Z. Rosensweig Genomics Research Center, HSS, NY) for consultation and help with data visualization. The work was supported by awards from NIH NIDA R21DA047936 and R03DA043428 (MS), R01DA035714 (JZ), NIH CA223956 (MW).
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MS, IS, MDW, JZ initiated the study, JS and IS developed software and performed literature mining, MA, CB, DO, ML, MS, MDW designed and performed experiments, CB and EP performed statistical analysis, HJ and MS performed bioinformatics analysis, VS helped with image acquisition and image analysis, JRT, SL, EB and JZ helped with data analysis and provided critical suggestions, MA, MDW, IS, and MS wrote the manuscript.
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Aksenova, M., Sybrandt, J., Cui, B. et al. Inhibition of the Dead Box RNA Helicase 3 Prevents HIV-1 Tat and Cocaine-Induced Neurotoxicity by Targeting Microglia Activation. J Neuroimmune Pharmacol 15, 209–223 (2020). https://doi.org/10.1007/s11481-019-09885-8
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DOI: https://doi.org/10.1007/s11481-019-09885-8