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（IBD）患者对以下药物没有适当的反应： 现有的治疗和常规药物仍然受到感染或恶性肿瘤风险增加的限制， 药物抗体和高成本。最近的证据表明， 在IBD中观察到的是由肠道上皮完整性的丧失引发和维持，随后是生态失调， 伴随细菌移位和侵入。对维持上皮屏障完整性至关重要， 以及肠道微生物体内平衡和保护免受病原微生物的是粘膜免疫 系统芳香烃受体（AHR）是肠道免疫系统的重要调节因子， 过程，包括IL-22的表达，这是负责肠道组织完整性，上皮修复， 微生物体内平衡我们最近发现了一类新的高效和药物样AHR激动剂 衍生自吲哚-吡啶支架，其适合于口服给药， 药代动力学（PK）和药效学特征。在本提案中，我们打算： (1)确定基于吲哚-吡啶支架的第一代AHR激动剂的作用方式 肠道屏障功能障碍的补充模型。在调查的第一阶段，我们将确定 第一代候选药物通过调节粘膜修复或通过调节肠粘膜修复来介导肠修复的程度 免疫应答或通过对肠炎补充小鼠模型中上皮的直接作用。在 在第二阶段，将进一步评估先导候选药物增强肠道完整性的能力， 初级肠道类器官，以及通过使用肠道类器官/免疫细胞共培养模型。 (2)全身暴露有限的肠道选择性AHR激动剂的设计。我们相信设计 限制AHR系统激活的策略将进一步增强这类重要药物的安全性。 化合物.我们建立的先导化合物将被用作母体结构，以探索 取代基，以及前药的设计，减少全身暴露。可下药的化学物质 空间将被限定以确保成功鉴定肠选择性AHR激动剂，其显示优先 在有限的全身暴露下激活肠组织中的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)表征精氨酸选择性AHR激动剂在肠道屏障小鼠模型中的有效性 功能障碍确定精氨酸选择性AHR激动剂用于预防和 IBD的治疗将是这些研究初始阶段的重点。化合物疗效将在 在预防和干预方案中增加补充性小鼠肠炎模型。我们将 随后确定安全性特征，包括遗传毒性、脱靶选择性和剂量依赖性 毒性的铅肠道选择性化合物，这表明显着的体内效力和功效。