Developing Chemical Probes for Inflammatory Pain

开发炎症性疼痛的化学探针

• 批准号: 10414636
• 负责人: Bahaa ElDien Elgendy
• 金额: $ 63.68万
• 依托单位: ST. LOUIS COLLEGE OF PHARMACY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10414636
• 关键词: Adrenal Cortex Hormones; Affect; Agonist; American; Binding; Biochemical; Biological Assay; Biology; Cells; Characteristics; Chemicals; Chronic; Chronic inflammatory pain; Clinical Trials; Coupled; Data; Degenerative polyarthritis; Development; Diabetes Mellitus; Docking; Functional disorder; G-Protein-Coupled Receptors; Goals; Human; Hypersensitivity; In Vitro; Inflammasome; Inflammation; Inflammatory; Interleukin-1; Interleukin-18; Ligands; Link; Manuscripts; Mechanics; Mediating; Metabolism; Modeling; Molecular; Mus; Nerve Tissue; Neuropathy; Non-Steroidal Anti-Inflammatory Agents; Nuclear Proteins; Nuclear Receptors; Obesity; Opioid; Pain; Pharmacology; Physiological; Physiological Processes; Physiology; Protein Isoforms; Regulation; Reproduction; Research; Research Personnel; Research Project Grants; Rewards; Role; Safety; Site; Stimulus; Structure; Techniques; Testing; Therapeutic; Transcription Repressor; addiction liability; base; cell injury; chronic pain; chronic pain patient; chronic painful condition; cytokine; design; drug discovery; efficacy testing; in vivo; inflammatory pain; innovation; macrophage; mouse model; nerve damage; non-opioid analgesic; novel; pain symptom; painful neuropathy; pre-clinical; receptor; screening; side effect; small molecule; targeted treatment; therapeutic target; tool; transcription factor; virtual screening

SUMMARY Chronic inflammation affects millions of Americans each year and can manifest in a variety of chronic pain conditions where normally innocuous stimuli produce pain symptoms. Long-term use of current pain therapeutics, including NSAIDS, corticosteroids, and opioids, can cause unwanted side effects, and addiction potential can limit their utilization. Recent studies have demonstrated a clear link between chronic low-grade inflammation and the increase in Chronic Inflammatory Pain (CIP) conditions. Alternative therapeutic targets are needed for the treatment of these painful conditions. Nuclear receptors, ligand-activated transcription factors that regulate a variety of physiological processes including metabolism, inflammation, reproduction, and development, represent key drug discovery targets (second to GPCRs). The REV-ERB proteins are nuclear receptors which function as transcriptional repressors and direct regulators of NLRP3 inflammasome components and proinflammatory cytokines (IL-1, IL-18), and regulate the activity of macrophages at sites of cellular damage. To date, the role of REV-ERB in relation to the manifestation of chronic pain symptoms has not been elucidated. Due to its role in NLRP3 inflammasome and proinflammatory cytokine regulation, we hypothesize that REV-ERB is a viable drug target for the treatment of inflammatory pain. Our strategy will leverage the known physiological functions of REV-ERB in chronic inflammation and use a chemical biology approach to identify novel REV-ERB ligands, with superior pharmacological profiles, to advance this potential therapy toward clinical trials. Our new preliminary data shows that total loss of REV-ERB in mice increases mechanical hypersensitivity. Our previous studies demonstrated that pharmacological activation of REV-ERB had no negative effects in preclinical mouse reward models, suggesting that targeting of REV-ERB may benefit many chronic pain conditions.

总结 慢性炎症每年影响数百万美国人，并可表现为各种慢性疼痛状况 通常无害的刺激会产生疼痛症状。长期使用目前的疼痛治疗药物，包括NSAIDS， 皮质类固醇和阿片类药物可引起不想要的副作用，并且成瘾性可能限制它们的利用。最近 研究表明，慢性低度炎症与慢性炎症增加之间存在明确的联系。 疼痛（CIP）状况。需要替代的治疗靶点来治疗这些疼痛性病症。核 受体，配体激活的转录因子，调节包括代谢在内的多种生理过程， 炎症、生殖和发育代表了关键的药物发现靶点（仅次于GPCR）。REV-ERB 蛋白质是核受体，其作为转录阻遏物和NLRP 3炎性体的直接调节物起作用 细胞因子和促炎细胞因子（IL-1 β，IL-18），并调节巨噬细胞的活性， 损害迄今为止，REV-ERB在慢性疼痛症状表现中的作用尚未阐明。 由于REV-ERB在NLRP 3炎性体和促炎细胞因子调节中的作用，我们假设REV-ERB是一种免疫调节因子。 治疗炎症性疼痛的可行药物靶点。我们的策略将利用已知的生理功能 REV-ERB在慢性炎症中的作用，并使用化学生物学方法鉴定新型REV-ERB配体，具有上级 药理学特征，以推进这种潜在的治疗走向临床试验。我们新的初步数据显示， 小鼠中REV-ERB β的丢失增加机械超敏性。我们以前的研究表明， REV-ERB的激活在临床前小鼠奖赏模型中没有负面影响，这表明靶向REV-ERB 可能有益于许多慢性疼痛病症。