Drug repurposing for the treatment of HIV-Associated Neurocognitive Disorder by AI-based literature mining

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 exacerbates 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. The list was narrowed to those with known small molecule inhibitors developed for other applications and lacking systemic toxicity in animal models. We tested the activity of small molecules targeted against the proteins of five prioritized genes to protect against the combined neurotoxicity of HIV-Tat and cocaine in primary neuronal cultures. Four prevented Tat and cocaine toxicity. The compounds are: the FDA approved drugs Amlexanox and Tazemetostat (EPZ-6438), Itaconate and Senicapoc. Despite the disparate molecular targets of these drugs, analysis revealed a common mechanism of neuroprotection; namely that modulation of astrocyte and microglia status prevents the toxicity of Tat and cocaine. To investigate the effects of the compounds (i) Rat Primary Neuronal cultures were treated with or without HIV-Tat for 48 hours in the presence or absence of small molecules or vehicle control (ii) The culture had been treated with cocaine for the next 24 hours. Upon treatment cells were lyzed followed by RNA purification Experiments had been performed in triplicates. Small molecule compounds used in experiment are senicapoc, 4-octyl-itaconate, amlexanox and tazemetostat. Concentrations of the compounds, HIV-Tat protein and cocaine is described in samples description table.