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Development of NLRP3 inhibitors for HIV-associated neuroinflammation

开发治疗 HIV 相关神经炎症的 NLRP3 抑制剂

基本信息

批准号：
10650871
负责人：
MICHAEL Ilya BUKRINSKY
金额：
$ 23.61万
依托单位：
HOWARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10650871
关键词：
Adaptor Signaling Protein Affect Antiviral Therapy Apoptosis Area Astrocytes Behavioral Binding Biochemical Biological Brain CASP1 gene Cell Line Cessation of life Chemicals Chronic Clinical Research Computer Assisted Computer-Aided Design Dementia Development Drug Design Drug usage Exploratory/Developmental Grant Foundations Functional disorder Future Goals HIV HIV Infections HIV-1 HIV-associated neurocognitive disorder IL18 gene In Vitro Individual Infection Inflammasome Inflammation Inflammatory Innate Immune System Interdisciplinary Study Interleukins Investigation Lead Leucine-Rich Repeat Licorice Life Expectancy Mediating Memory Microglia Modeling Molecular Neurocognitive Neurons Nucleotides Pathogenesis Pathogenicity Pathway interactions Patients Pattern Pharmaceutical Chemistry Play Preclinical Drug Development Process Proteins Publications Reporting Research Role Series Signal Transduction Structure Sulfonylurea Compounds Testing Therapeutic Toxic effect Transgenic Mice Translational Research Virus Diseases analog antiretroviral therapy chemical stability comorbidity computer studies cytokine cytokine release syndrome drug development drug discovery druggable target humanized mouse improved in vitro Assay in vitro activity in vitro testing in vivo in vivo evaluation inhibitor innovation lead candidate marenostrin mouse model neurocognitive disorder neuroinflammation neuron loss neuropathology novel novel therapeutics nucleotide receptor pathogen pharmacophore preclinical development prevent response screening small molecule

项目摘要

ABSTRACT The advent of effective combination antiretroviral therapies (cART) has increased the life expectancy for HIV-1 patients, however, these patients are still prone to comorbidities, such as HIV-associatiated neurocognitive disorders (HAND), which affect up to 50% of HIV-infected individuals. Persistent inflammation due to the overactivation of the innate immune system is one of the main underlying causes of HAND. Nucleotide binding domain, leucine rich repeat pyrin domain containing protein-3 (NLRP3) inflammasome has emerged as a druggable target for the management of HIV-1-associated neuropathologies. The NLRP3 inflammasome is shown to be activated in response to a wide array of pathogen- and danger-associated molecular patterns (PAMPs and DAMPs, respectively). A key step in the activation process is a homotypic interaction between the pyrin domains in NLRP3 and an adapter protein, apoptosis-associated speck-like protein containing a CARD (ASC). NLRP3 activation leads to the release of pro-inflammatory cytokines, such as, interleukin-1 (IL-1) and IL-18, causing neuronal pyroptosis and death. Disruption of NLRP3 signaling via small molecules, such as MCC950, is reported to display beneficial effects in the transgenic mouse models. Our recent studies identified a small molecule, AMS-17, that thwarted the NLRP3 activation in N9 microglia both in vitro and in vivo. Subsequent mechanistic analysis revealed that the NLRP3 inhibitory activity of AMS-17 is attributed to its ability to bind to NLRP3 pyrin domain, thus preventing the interaction between NLRP3 and ASC. This proposal is focused on developing AMS-17 analogues with improved biological activity, low toxicity, and high drug-likeness. Aim 1 described in this proposal is focused on the computer-assisted design, synthesis and chemical characterization of AMS-17 analogues. Aim 2 will involve testing of the lead candidates in the humanized mouse model of HAND. The proposed studies are highly significant since they will provide new therapeutic options to minimize HIV-associated neurocognitive dysfunction. The proposal incorporates expertise in the area of synthetic medicinal chemistry (Dr. Kulkarni), biological screening (Dr. Bukrinsky), and computer-assisted drug design (Dr. Adzhubei). It is fully consistent with the goals of this RFA and is expected to define NLRP3 inhibitory compounds working through a novel mechanism different from that of any other currently used drug.

摘要