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.

中文翻译：

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抑制 Dead Box RNA 解旋酶 3 通过靶向小胶质细胞激活来预防 HIV-1 Tat 和可卡因诱导的神经毒性。


HIV-1 相关神经认知障碍 (HAND) 是 HIV 感染的一种常见且临床上有害的并发症。受感染细胞释放的病毒蛋白（包括 Tat）会引起神经元毒性。 HIV 感染者的药物滥用极大地影响了神经元损伤的严重程度。为了将小分子抑制剂重新用于抗 HAND 治疗，我们采用了 MOLIERE，这是我们开发的基于人工智能的文献挖掘系统。 MOLIERE 对所有人类基因进行了分析和优先排序，以找到与 HAND 有关的先前未知的目标。从已确定的高优先级基因中，我们将范围缩小到那些具有为其他应用而开发的已知小分子配体且在动物模型中缺乏全身毒性的基因。为了验证基于 AI 的过程，选择了 DDX3 解旋酶活性的选择性小分子抑制剂 RK-33，并测试了其神经保护活性。该化合物先前是为癌症治疗而开发的，经过测试可预防 HIV Tat 和可卡因的联合神经毒性。啮齿动物皮层培养物用 6 或 60 ng/ml 的 HIV Tat 和 10 或 25 μM 可卡因处理，这会引起显着的毒性。 RK-33 剂量低至 1 μM 即可大大降低 Tat 和可卡因的神经毒性。转录组分析表明，大多数 Tat 激活的转录本都是小胶质细胞特异性基因，而 RK-33 会​​阻断它们的激活。 RK-33 治疗可抑制小胶质细胞和促炎细胞因子 IL-6、TNF-α、MCP-1/CCL2、MIP-2、IL-1α 和 IL-1β 的数量和大小的 Tat 和可卡因依赖性增加。这些发现表明，抑制 DDX3 不仅有可能治疗手部疾病，而且有可能治疗其他神经退行性疾病。

RK-33 是 Dead Box RNA 解旋酶 3 (DDX3) 的选择性抑制剂，通过抑制小胶质细胞活化和促炎细胞因子的产生，保护神经元免受 Tat 和可卡因联合神经毒性的影响。