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

HIV 诱导的突触树突损伤/白细胞信息的非 I 型激酶抑制

• 批准号: 8071793
• 负责人: Val S. Goodfellow
• 金额: $ 25.53万
• 依托单位: CALIFIA BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-15 至 2012-03-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8071793
• 关键词: AIDS neuropathy; AIDS/HIV problem; Active Sites; Age; Aging; Animal Model; Architecture; Autopsy; Binding; Biological Assay; Brain imaging; CCL2 gene; Cell model; Cells; Cerebrospinal Fluid; Chemotactic Factors; Clinical; Cognition; Collaborations; Data; Dementia; Development; Disease; Dose; Drug Kinetics; Exhibits; Family; Functional disorder; Future; Goals; HIV; HIV Infections; HIV-1; Homology Modeling; Human; IL8 gene; Image; Immune; In Vitro; Individual; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Intellectual Property; Interleukin-6; Interruption; Knowledge; Lead; Leukocytes; Life; Mediator of activation protein; Medical center; Memory; Mental disorders; Microsomes; Mitogen-Activated Protein Kinase Kinases; Modeling; Molecular; Molecular Models; Motor; Mus; Neuraxis; Neurocognitive; Neuroglia; Neurologic; Neuropathogenesis; Neuropathy; Neurotoxins; Oral; Pathologic Processes; Pathway interactions; Patients; Pattern; Penetration; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phosphotransferases; Play; Population; Prevalence; Production; Property; Publishing; Role; Scanning; Series; Signal Pathway; Signal Transduction; Small Business Innovation Research Grant; Specificity; Structure; Structure-Activity Relationship; Supportive care; Symptoms; Synapses; TNF gene; Techniques; Testing; Therapeutic; United States; Universities; Up-Regulation; Viral; Viral Load result; Virus Diseases; Work; analog; antiretroviral therapy; brain tissue; chemokine; commercialization; cross reactivity; cytokine; drug discovery; experience; family structure; follow-up; high throughput screening; immune function; in vivo; inhibitor/antagonist; kinase inhibitor; lead series; macrophage; mixed lineage kinase 3; molecular modeling; monocyte; mouse model; nervous system disorder; neuroinflammation; novel; patch clamp; patient population; phase 1 study; prevent; pyridine; research study; safety study; scaffold; small molecule

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.

描述（由申请人提供）：抗逆转录病毒疗法（CART）的结合减慢了发作，但并未改变HIV - 相关神经疾病的患病率。在衰老的患者人群中，尽管手推车能够减少CNS的病毒载量至无法检测到的水平，但HIV-1相关神经认知障碍（HARD）的患病率可能正在增加，因此患有HIV的一半人可能会出现手的症状。手的标志包括：1）炎性细胞因子和趋化因子的失调，2）2）免疫细胞（单核细胞）募集到中枢神经系统（CNS），3），3）神经胶质感染导致其正常功能中断和4）广泛的突触刺激性损害。这次喀斯喀特与许多炎症介体有关，TNF-1释放和信号传导可能起着主要的中心作用。在手脊髓液和手部患者的脑脊液后脑组织中，介体的一个更有限的子集被确定为上调。这些经过翻译验证的介体/效应子包括TNF-1，单核细胞趋化剂MCP-1和混合细胞激酶3（MLK3），这是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博士和Stephen Dewhurst合作，我们确定了URMC-099，该化合物抑制MLK3并阻止MCP-1和TNF-1和TNF-1的上调以及HIV-1 TAT刺激的人类巨噬细胞中MCP-1和TNF-1和其他炎症媒介。罗切斯特大学（University of Rochester Team）开发了一种体内成像测定法，以评估HIV神经毒素和潜在药物的影响，从而可以改善其作用。暴露于HIV-1 TAT的小鼠中的体内脑成像实验表明，腹腔URMC-099的给药可防止TAT诱导的白细胞浸润和小胶质细胞激活，并显着逆转TAT引起的突触结构的损害。突触体系结构的损害是损害认知和记忆的手的关键病理过程。 Califia Bio正在通过开发针对它们的小分子抑制剂来识别和验证主要的“控制枢纽”（即关键激酶）。我们假设具有针对MLK激酶家族的具有选择性活性的化合物，并且尚未确定的激酶可能更有可能成功地阻止疾病病理生理学的重要信号网络，而不是选择性地抑制MLK3的MLK3，该化合物仅由于MLK信号通路的功能冗余而应抑制MLK3。我们已经为URMC-099进行了活性范围。现在，我们还发现了具有非常不同的分子支架的铅MLK抑制剂，这些抑制剂无法在MLK激酶家族中使用相同的结合模式。该应用程序的目的是优化和表征这些新的铅序列，以干扰促炎性介体中心的促进介质，并确定最佳化合物所表现出的激酶抑制的模式。在第2阶段，我们将寻求在手动物模型中具有功效的开发化合物。 公共卫生相关性：该I阶段SBIR提案旨在发现潜在的小分子治疗剂来治疗与艾滋病毒/艾滋病相关的心理和神经系统疾病。 2007年，全球3320万人感染了艾滋病毒/艾滋病。在美国，据估计，超过100万人患有艾滋病毒，估计每年发生40,000名新的艾滋病毒感染。据估计，随着艾滋病毒感染的个体人群在抗逆转录病毒疗法的支持性护理下，这些患者中有多达50％会出现与HIV相关的神经系统疾病的症状，范围从严重的痴呆症到神经病和运动功能障碍。