Non-Type I Kinase Inhibition of HIV-Induced Synaptodendritic Damage/Leukocyte Inf

描述（由申请人提供）：联合抗逆转录病毒治疗（cART）减缓了HIV相关神经系统疾病的发病，但没有改变其患病率。在老年患者人群中，HIV-1相关神经认知障碍（HAND）的患病率可能会增加，尽管cART能够将CNS中的病毒载量降低至无法检测的水平，因此一半的HIV感染者可能会出现HAND症状。HAND的特点包括：1）炎性细胞因子和趋化因子的失调，2）免疫细胞（单核细胞）向中枢神经系统（CNS）的募集，3）神经胶质的病毒感染导致其正常功能的中断，和4）广泛的突触树突损伤。许多炎症介质参与了这一级联反应，其中TNF-1的释放和信号传导可能发挥主要的核心作用。已经鉴定了更有限的介体子集在HAND患者的脑脊液和死后脑组织中上调。这些经实验验证的介质/效应物包括TNF-1、单核细胞趋化因子MCP-1和混合谱系激酶3（MLK 3），后者是MAPK激酶调节的炎症途径中的重要控制点。与罗切斯特大学医学中心的Harris Gelbard和Stephen Dewhurst博士合作，我们已经确定了URMC-099，一种抑制MLK 3并阻断HIV-1达特刺激的人巨噬细胞中MCP-1和TNF-1及其他炎症介质上调的化合物。罗切斯特大学的研究小组开发了一种体内成像检测方法，以评估艾滋病毒神经毒素和可能改善其影响的潜在药物的影响。在脑内暴露于HIV-1达特的小鼠中的体内脑成像实验已经显示腹膜内施用URMC-099防止了塔特诱导的白细胞浸润和小胶质细胞活化，并显著逆转了塔特诱导的对突触结构的损伤。突触结构的损伤是HAND损伤认知和记忆的关键病理过程。Califia Bio正在通过开发针对HAND通路的小分子抑制剂来识别和验证主要的“控制中心”（即关键激酶）。我们假设，与选择性抑制MLK 3的化合物相比，对MLK激酶家族和尚未鉴定的激酶具有选择性活性的化合物可能更有可能成功阻断参与疾病病理生理学的重要信号网络，部分原因是MLK信号通路的功能冗余。我们已经对URMC-099的活性进行了激酶组宽筛选;我们现在还发现了具有非常不同的分子支架的前导MLK抑制剂，其不能利用MLK激酶家族中的相同结合模式。本申请的目的是优化和表征这些新的先导化合物系列干扰HAND核心促炎介质的能力，并鉴定最佳化合物表现出的激酶抑制模式。在第2阶段，我们将寻求开发在HAND动物模型中有效的化合物。 公共卫生相关性：该I期SBIR提案旨在发现治疗HIV/AIDS相关精神和神经障碍的潜在小分子疗法。2007年，全世界有3 320万人感染艾滋病毒/艾滋病。在美国，估计有100多万人感染艾滋病毒，估计每年有40，000例新的艾滋病毒感染。据估计，随着艾滋病毒感染者的年龄增长，在联合抗逆转录病毒治疗的支持性护理下，多达50%的这些患者将出现艾滋病毒相关神经系统疾病的症状，这些症状可能从严重的痴呆症到神经病和运动功能障碍。

DESCRIPTION (provided by applicant): Combination antiretroviral therapy (cART) has slowed the onset, but has not altered the prevalence of HIV - associated neurologic disease. In aging patient populations, the prevalence of HIV-1 associated neurocognitive disorder (HAND) may be increasing, despite the ability of cART to reduce viral load in the CNS to undetectable levels, such that half of the population living with HIV may experience symptoms of HAND. The hallmarks of HAND include: 1) a dysregulation of inflammatory cytokines and chemokines, 2) the recruitment of immune cells (monocytes) to the central nervous system (CNS), 3) the viral infection of glia leading to interruption of their normal function, and 4) extensive synaptodendritic damage. A host of inflammatory mediators are implicated in this cascade, where TNF-1 release and signaling likely play a major central role. A more limited subset of mediators has been identified as being up-regulated in the cerebrospinal fluid and post- mortem brain tissues of HAND patients. These translationally validated mediators/effectors include TNF-1, the monocyte chemoattractant MCP-1, and mixed-lineage kinase 3 (MLK3), an important control point in MAPK kinase regulated inflammation pathways. In collaboration with Dr. Harris Gelbard and Stephen Dewhurst at the University of Rochester Medical Center, we have identified URMC-099, a compound that inhibits MLK3 and blocks up-regulation of MCP-1 and TNF-1 and other inflammatory mediators in HIV-1 Tat stimulated human macrophages. The University of Rochester team has developed an in vivo imaging assay to evaluate the effects of HIV neurotoxins and potential drugs that may ameliorate their effects. In vivo brain imaging experiments in mice exposed intracerebrally to HIV-1 Tat have shown that i.p. administration of URMC-099 prevents Tat-induced leukocyte infiltration and microglial activation, and dramatically reverses Tat-induced damage to synaptic architecture. The damage to synaptic architecture is the key pathological process of HAND in damaging cognition and memory. Califia Bio is identifying and validating major "control hubs" (i.e. critical kinases) involved in the pathways leading to HAND by developing small molecule inhibitors directed against them. We hypothesize that a compound with selective activity against the MLK family of kinases, and as yet unidentified kinases, may be more likely to be successful in blocking important signaling networks involved in the pathophysiology of the disease than a compound that selectively inhibits only MLK3, due in part to the functional redundancy of MLK signaling pathways. We have conducted kinome wide screens of activity for URMC-099; we also have now discovered lead MLK inhibitors with very different molecular scaffolds that cannot utilize the same binding modes in the MLK family of kinases. The goal of this application is to optimize and characterize these new lead series for their ability to interfere with pro-inflammatory mediators central to HAND and to identify the patterns of kinase inhibition exhibited by the best compounds. In Phase 2 we will seek development compounds with efficacy in animal models of HAND. PUBLIC HEALTH RELEVANCE: This Phase I SBIR proposal is aimed at the discovery of potential small molecule therapeutics to treat HIV/AIDS-associated mental and neurological disorders. In 2007, 33.2 million people worldwide were infected with HIV/AIDS. In the United States, it is estimated that more than 1 million individuals live with HIV, and an estimated 40,000 new HIV infections occur each year. It is estimated that as the population of HIV infected individuals ages, under the supportive care of combined antiretroviral therapy, as many as 50 percent of these patients will experience symptoms of HIV-associated neurological disease, which may range from severe dementia, to neuropathies and motor dysfunction.