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: 10420534
• 负责人: Elliot Chaikof
• 金额: $ 70.58万
• 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/10420534
• 关键词: Adaptor Signaling Protein; Adult; Agonist; Antibodies; Aryl Hydrocarbon Receptor; Bacterial Translocation; Biodistribution; Cells; Chemicals; Coculture Techniques; Colitis; Dose; Drug Design; Effectiveness; Ensure; Epithelial; 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; Investigation; Lead; Ligands; Maintenance; Malignant Neoplasms; Mediating; Modeling; Mucosal Immune Responses; Mucosal Immune System; Mucous Membrane; Mus; Oral; Oral Administration; Organoids; Parents; Pathogenicity; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Plants; 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; base; 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; 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 至少三分之一的炎症性肠病(IBD)患者对 现有的治疗方法和常规药物仍然受到感染或恶性肿瘤风险增加的限制，抗- 药物抗体，且成本高。最近的证据表明，加剧的炎症反应 在IBD中观察到的是通过肠道上皮完整性的丧失以及随之而来的生物失调和 伴随着细菌移位和入侵。对于维持上皮屏障的完整性至关重要，因为 以及肠道微生物的动态平衡和对病原微生物的保护是粘膜免疫 系统。芳香烃受体(AHR)是肠道免疫系统的重要调节器，在肠道免疫系统中发挥重要的调节作用。 过程，包括IL-22的表达，这是负责肠道组织完整性、上皮修复和 微生物动态平衡。我们最近发现了一类新的高效和类药物AHR激动剂 从吲哚-吡啶类支架衍生而来，适合于口服给药并显示出良好的前景 药代动力学(PK)和药效学概况。在这项建议中，我们打算： (1)确定基于吲哚-吡啶支架的第一代AHR激动剂的作用模式 在肠道屏障功能障碍的补充模型中。在我们调查的第一阶段，我们将确定 第一代候选药物通过调节粘膜或粘膜在多大程度上介导肠道修复 免疫反应或通过对补充性小鼠肠炎模型上皮细胞的直接作用。在 第二阶段，将进一步评估候选先导药物增强肠道完整性的能力 原代肠道类器官，以及通过使用肠道类器官/免疫细胞共培养模型。 (2)肠道选择性AHR激动剂的设计。我们相信这个设计 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。我们已建立的先导化合物将被用作母体结构，以探索加入 取代基，以及前药的设计，减少全身暴露。可下药的化学物质 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 在有限全身暴露的情况下激活肠道组织中的AHR。我们将证实IL-22在人T细胞中的诱导作用 来自健康成人和活动性IBD成人的细胞。 (3)肠选择性AHR激动剂在小鼠肠屏障模型中的作用 功能障碍。明确肠道选择性AHR激动剂预防和治疗高血压的疗效 IBD的治疗将是这些研究的初始阶段的重点。将在#年评估复合药效。 预防和干预方案中补充的肠炎小鼠模型。我们会 随后确定安全性，包括遗传毒性、靶外选择性和剂量依赖性 铅肠道选择性化合物的毒性，这些化合物显示出显著的体内效力和疗效。