Structure-Guided Design of Intestine-Selective AHR Agonists for Restoration of Gut Barrier Integrity in IBD

用于恢复 IBD 肠道屏障完整性的肠道选择性 AHR 激动剂的结构引导设计

• 批准号: 10627922
• 负责人: Elliot Chaikof
• 金额: $ 70.59万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10627922
• 关键词: Acceleration; Adaptor Signaling Protein; Adult; Agonist; Antibodies; Aryl Hydrocarbon Receptor; Bacterial Translocation; Biodistribution; Cells; Chemicals; Coculture Techniques; Colitis; Dose; Drug Design; Effectiveness; Ensure; Epithelium; Exhibits; Functional disorder; Generations; Genetic Polymorphism; Gut Mucosa; Homeostasis; Human; Immune; Immune system; Immunity; Immunologic Receptors; Immunomodulators; Indoles; Infection; Inflammatory Bowel Diseases; Inflammatory Response; Innate Immune System; Intervention; Intestines; Invaded; Investigation; Lead; Ligands; Maintenance; Malignant Neoplasms; Mediating; Modeling; Mucosal Immune Responses; Mucosal Immune System; Mucous Membrane; Mus; Oral Administration; Organoids; Parents; Pathogenicity; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Predisposition; Prevention; Process; Production; Protocols documentation; Reporting; Risk; Safety; Science; Signal Transduction; Structure; Susceptibility Gene; T-Lymphocyte; Therapeutic; Tissues; Toxic effect; Treatment Efficacy; aryl hydrocarbon receptor ligand; computer studies; cost; design; dietary; disorder risk; drug candidate; dysbiosis; enteritis; epithelial repair; experimental study; gastrointestinal epithelium; genome wide association study; genotoxicity; healing; in vivo; infection risk; interleukin-22; intestinal epithelium; lead optimization; microbial; microorganism; mouse model; murine colitis; pharmacokinetics and pharmacodynamics; plant metabolites; pyridine; rational design; repaired; restoration; scaffold

Project Summary At least one-third of patients with inflammatory bowel disease (IBD) do not respond appropriately to existing therapies and conventional agents remain limited by an increased risk of infection or malignancy, anti- drug antibodies, and high cost. Recent evidence now suggests that the exacerbated inflammatory response observed in IBD is initiated and maintained by loss of gut epithelial integrity with an ensuing dysbiosis and accompanying bacterial translocation and invasion. Crucial to the maintenance of epithelial barrier integrity, as well as gut microbial homeostasis and protection from pathogenic microorganisms is the mucosal immune system. The aryl hydrocarbon receptor (AHR) is an essential regulator of the gut immune system and mediates processes, including the expression of IL-22, which are responsible for gut tissue integrity, epithelial repair, and microbial homeostasis. We have recently discovered a new class of highly potent and drug-like AHR agonists derived from an indole-pyridine scaffold, which are suitable for oral administration and display promising pharmacokinetic (PK) and pharmacodynamics profiles. In this proposal we intend to: (1) Determine the modes of action of first-generation AHR agonists based on an indole-pyridine scaffold in complementary models of gut barrier dysfunction. In the first phase of our investigations, we will define the extent to which first-generation drug candidates mediate intestinal repair by modulating either the mucosal immune response or through a direct effect on the epithelium in complementary mouse models of enteritis. In the second phase, the ability of lead drug candidates to enhance intestinal integrity will be further evaluated using primary gut organoids, as well as through the use of gut organoid/immune cell co-culture models. (2) Design of intestine-selective AHR agonists with limited systemic exposure. We believe that design strategies that limit systemic activation of AHR will further enhance the safety profile of this important class of compounds. Our established lead compounds will be used as parent structures to explore the incorporation of substituents, as well as the design of antedrugs, which reduce systemic exposure. The druggable chemical space will be defined to ensure successful identification of gut-selective AHR agonists that display preferential activation of AHR in intestinal tissue with limited systemic exposure. We will confirm IL-22 induction in human T cells from healthy adults and adults with active IBD. (3) Characterize the effectiveness of intestine-selective AHR agonists in murine models of gut barrier dysfunction. Defining the therapeutic efficacy of intestine-selective AHR agonists for the prevention and treatment of IBD will be focus of the initial phase of these studies. Compound efficacy will be assessed in additional complementary murine models of enteritis in both prevention and intervention protocols. We will subsequently determine the safety profile, including genotoxicity, off-target selectivity, and dose-dependent toxicity for lead gut-selective compounds, which demonstrate significant in vivo potency and efficacy.

项目摘要 至少有三分之一的炎症性肠病患者（IBD）对 现有的疗法和常规药物仍然受到感染或恶性肿瘤的风险增加，抗 药物抗体和高成本。现在最近的证据表明炎症反应加剧 在IBD中观察到的是由于失去肠道上皮完整性而启动和维护的，随后的营养不良和 伴随细菌易位和入侵。对于维持上皮屏障完整性至关重要， 以及肠道微生物稳态和防止致病性微生物的保护是粘膜免疫 系统。芳基碳氢化合物受体（AHR）是肠道免疫系统的重要调节剂，并介导 过程，包括肠道组织完整性，上皮修复和 微生物稳态。我们最近发现了一类新的高效和类似毒品的AHR激动剂 源自吲哚 - 吡啶支架，适合口服和显示有希望的 药代动力学（PK）和药效学概况。在此提案中，我们打算： （1）根据吲哚 - 吡啶支架确定第一代AHR激动剂的作用模式 在肠道屏障功能障碍的互补模型中。在调查的第一阶段，我们将定义 第一代候选药物在多大程度上通过调节粘膜调节intestinal修复 免疫反应或通过互补小鼠肠炎模型中上皮的直接影响。在 第二阶段，将使用铅药物提高肠道完整性的能力进一步评估 一级肠道类器官，以及肠道类器官/免疫细胞共培养模型。 （2）设计有限的全身性暴露的肠道选择性AHR激动剂。我们相信设计 限制AHR系统性激活的策略将进一步提高这一重要类别的安全性 化合物。我们既定的铅化合物将用作探索合并的父结构 取代基以及抗甲基的设计，可以减少全身性暴露。可药化学物质 将定义空间以确保成功识别显示优先的肠道选择性AHR激动剂 在全身暴露有限的肠道组织中AHR的激活。我们将确认人类t的IL-22诱导 来自健康成年人和活跃IBD的成年人的细胞。 （3）表征肠道选择性AHR激动剂在肠道壁垒模型中的有效性 功能障碍。定义肠道选择性AHR激动剂的治疗功效，以预防和 IBD的处理将是这些研究初始阶段的重点。复合功效将在 预防和干预方案中的其他互补鼠肠炎模型。我们将 随后确定安全概况，包括遗传毒性，脱靶的选择性和剂量依赖性 铅肠道选择性化合物的毒性，表现出显着的体内效力和功效。