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

描述(申请人提供)：联合抗逆转录病毒疗法(CART)延缓了发病，但并未改变HIV相关神经疾病的流行。在老龄化患者群体中，HIV-1相关神经认知障碍(HAND)的患病率可能会增加，尽管CART有能力将CNS中的病毒载量降低到无法检测的水平，以至于一半的艾滋病毒携带者可能会出现手部症状。手部的特征包括：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)募集，3)神经胶质细胞的病毒感染导致其正常功能中断，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，其中肿瘤坏死因子-1的释放和信号可能发挥了重要的核心作用。在手部患者的脑脊液和死后脑组织中，有一组更有限的介质被确定为上调表达。这些翻译验证的介质/效应物包括单核细胞趋化因子MCP-1和MAPK激酶调节的炎症通路中的一个重要控制点--混合谱系激酶3(MLK3)。在罗彻斯特大学医学中心的Harris Gelbard博士和Stephen Dehuurst博士的合作下，我们已经确定了URMC-099，这是一种化合物，可以抑制MLK3，并阻止HIV-1 TAT刺激的人巨噬细胞中MCP-1、TNF-1和其他炎症介质的上调。罗切斯特大学的研究小组开发了一种体内成像分析方法，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效果。脑内暴露于HIV-1TAT的小鼠的活体脑成像实验表明，I.P.给予URMC-099可阻止TAT诱导的白细胞渗透和小胶质细胞激活，并显著逆转TAT诱导的突触结构损伤。突触结构的损伤是手损伤认知和记忆的关键病理过程。卡利菲亚生物公司正在通过开发针对它们的小分子抑制剂来识别和验证导致Hand的通路中涉及的主要“控制中枢”(即关键激酶)。我们假设，与仅选择性抑制MLK3的化合物相比，具有选择性活性的化合物可能更有可能成功地阻断参与疾病病理生理的重要信号网络，部分原因是MLK信号通路的功能冗余。我们已经对URMC-099进行了动态组广泛的活性筛选；我们现在还发现了具有非常不同的分子支架的铅MLK抑制剂，它们不能利用MLK家族中相同的结合模式。这项应用的目标是优化和表征这些新的先导系列，以确定它们干扰手部中心促炎介质的能力，并确定最佳化合物表现出的激酶抑制模式。在第二阶段，我们将在手的动物模型中寻找具有疗效的开发化合物。 公共卫生相关性：这项第一阶段SBIR建议旨在发现潜在的小分子疗法来治疗艾滋病毒/艾滋病相关的精神和神经疾病。2007年，全世界有3320万人感染了艾滋病毒/艾滋病。在美国，估计有100多万艾滋病毒携带者，每年估计有4万人新感染艾滋病毒。据估计，随着艾滋病毒感染者人口的老龄化，在联合抗逆转录病毒治疗的支持性护理下，多达50%的患者将出现艾滋病毒相关神经疾病的症状，从严重的痴呆症到神经疾病和运动功能障碍。

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.