Inhibition of the Dead Box RNA Helicase 3 Prevents HIV-1 Tat and Cocaine-Induced Neurotoxicity by Targeting Microglia Activation.
Inhibition of the Dead Box RNA Helicase 3 Prevents HIV-1 Tat and Cocaine-Induced Neurotoxicity by Targeting Microglia Activation.
复制标题
DOI：
10.1007/s11481-019-09885-8
复制
发表时间：
2020-06
期刊：
影响因子：
--
通讯作者：
Shtutman M
中科院分区：
文献类型：
--
作者：
Aksenova M;Sybrandt J;Cui B;Sikirzhytski V;Ji H;Odhiambo D;Lucius MD;Turner JR;Broude E;Peña E;Lizarraga S;Zhu J;Safro I;Wyatt MD;Shtutman M
HIV-1相关性神经认知障碍（HAND）是HIV感染的常见和临床有害并发症。病毒蛋白质，包括达特，从受感染的细胞释放，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，我们采用了我们开发的基于AI的文献挖掘系统MOLIERE。MOLIERE对所有人类基因进行了分析和优先排序，以找到与HAND相关的先前未知的靶点。从鉴定的高优先级基因中，我们将列表缩小到具有为其他应用开发的已知小分子配体并且在动物模型中缺乏全身毒性的那些。为了验证基于AI的过程，选择DDX 3解旋酶活性的选择性小分子抑制剂RK-33并测试其神经保护活性。这种化合物以前是为治疗癌症而开发的，现在被测试用于预防艾滋病毒达特和可卡因的联合神经毒性。用6或60 ng/ml HIV达特和10或25 μM可卡因处理啮齿类动物皮质培养物，这会引起大量毒性。RK-33在低至1 μM的剂量下大大降低了达特和可卡因的神经毒性。转录组分析表明，大多数Tat激活的转录本是小胶质细胞特异性基因，RK-33阻断了它们的激活。RK-33治疗可抑制小胶质细胞数量和大小的达特和可卡因依赖性增加以及促炎细胞因子IL-6、TNF-α、MCP-1/CCL 2、MIP-2、IL-1α和IL-1β。这些发现表明，DDX 3的抑制可能不仅具有治疗HAND的潜力，还具有治疗其他神经退行性疾病的潜力。
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.
登录
查看更多内容
影响因子：
4.6
作者：
Davis BM;Salinas-Navarro M;Cordeiro MF;Moons L;De Groef L
通讯作者：
De Groef L
影响因子：
2.5
作者：
BENNETT, BA;HYDE, CE;CLODFELTER, JE
通讯作者：
CLODFELTER, JE
影响因子：
16.2
作者：
Chandra R;Engeln M;Schiefer C;Patton MH;Martin JA;Werner CT;Riggs LM;Francis TC;McGlincy M;Evans B;Nam H;Das S;Girven K;Konkalmatt P;Gancarz AM;Golden SA;Iñiguez SD;Russo SJ;Turecki G;Mathur BN;Creed M;Dietz DM;Lobo MK
通讯作者：
Lobo MK
影响因子：
2.4
作者：
Bertrand, Sarah J.;Aksenova, Marina V.;Booze, Rosemarie M.
通讯作者：
Booze, Rosemarie M.
影响因子：
25
作者：
Butovsky, Oleg;Jedrychowski, Mark P.;Moore, Craig S.;Cialic, Ron;Lanser, Amanda J.;Gabriely, Galina;Koeglsperger, Thomas;Dake, Ben;Wu, Pauline M.;Doykan, Camille E.;Fanek, Zain;Liu, LiPing;Chen, Zhuoxun;Rothstein, Jeffrey D.;Ransohoffl, Richard M.;Gygi, Steven P.;Antel, Jack P.;Weiner, Howard L.
通讯作者：
Weiner, Howard L.