Second generation GLP-1 agonists without nausea/emesis side effects

第二代 GLP-1 激动剂，无恶心/呕吐副作用

• 批准号: 10577892
• 负责人: Bart C DE JONGHE
• 金额: $ 59.28万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10577892
• 关键词: Acute; Agonist; Amaze; Anatomy; Animal Model; Animals; Attention; Automobile Driving; Behavior; Behavioral; Beta Cell; Binding; Binding Proteins; Biological Assay; Blood; Blood Glucose; Body Weight; Body Weight decreased; Brain; Brain Stem; Cachexia; Carrier Proteins; Cell Line; Central Nervous System; Chemicals; Chronic; Clinical; Complex; Cystic Fibrosis; Data; Diabetes Mellitus; Diagnosis; Disease; Dorsal; Dose; Drug Kinetics; Eating; Economic Burden; Emetics; Epidemic; Event; FDA approved; Family; GCG gene; GLP-I receptor; Gastric Emptying; Generations; Glucagon; Glucose tolerance test; HIV; Health Care Costs; Hormones; Human; Hyperglycemia; Hypoglycemia; Hypothalamic structure; In Vitro; Incidence; Insulin; Intake; Intestines; Intracellular Transport; Intrinsic factor; Kaolin; Life; Ligands; Malaise; Malignant Neoplasms; Mammals; Marketing; Mediating; Mediator; Medical; Modeling; Mus; Nausea; Nausea and Vomiting; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Pancreas; Patients; Pattern; Penetrance; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacopoeias; Pharmacotherapy; Physiological; Population; Prognosis; Public Health; Publishing; Quality of life; Rattus; Reporting; Research; Rodent Model; Role; Shrews; Sick Role; Site; Structure of beta Cell of islet; Testing; Therapeutic; Therapeutic Effect; Thinness; Tissues; Transcobalamins; United States; Vagus nerve structure; Vitamin B 12; Vomiting; analog; cobinamide; comorbidity; compliance behavior; design; diet-induced obesity; economic cost; euglycemia; exenatide; experience; experimental study; glucagon-like peptide 1; glycemic control; human model; improved; in vivo; incretin hormone; inhibitor; innovation; insulin secretion; meter; mouse model; novel; pharmacologic; pre-clinical; pre-clinical assessment; reduced food intake; side effect; subcutaneous; virtual

Project Summary The proposed research of this R01 application focuses on creating a second-generation glucagon-like peptide- 1 (GLP-1)-based pharmaceutical that retains all of the blood glucose lowering profiles but completely eliminates the major side effects of nausea, vomiting and malaise. Such side effects, along with hypophagia, are produced by existing GLP-1R agonists due to central nervous system (CNS) penetrance and direct action in the brain. Thus, we sought to create GLP-1R agonists with reduced brain penetrance but with the full potent pharmacodynamic profile on pancreatic GLP-1R populations. Our novel preliminary data convincingly demonstrate the ability of a vitamin B12 (B12) conjugate of the GLP1-R agonist Exendin-4 (Ex4), namely (B12- Ex4), to produce hypoglycemia in a glucose tolerance test (GTT) in both mouse and rat models without producing hypophagia or nausea/malaise. This glucoregulation without nausea/malaise appears to be due to a virtual absence of ligand penetrance into the CNS, a hypothesis supported by radiolabelled B12 studies showing extremely low levels of B12 entry into the brain, as well as immunohistochemical analyses of fluorescently- tagged B12-Ex4 in comparison to native Ex4 at the site of CNS activation. This application therefore tests the following specific aims to both enhance the preclinical assessment of B12-Ex4 as a second-generation T2DM therapeutic and test the hypothesis that the total portfolio of therapeutic effects that exploit the `B12-family' can be enhanced by conjugation of Ex4 to a fragment of B12, specifically cobinamide (Cbi), which targets Haptocorrin (HC), a Cbi binding protein found only in mammals, including humans: [1] Characterizes the physiological, behavioral and anatomical mechanisms mediating the hypoglycemic effects of B12-Ex4 without the incidence of hypophagia and nausea/malaise using both lean/euglycemic and obese/hyperglycemic rat and mouse models; [2] Conducts systematic in vitro and in vivo analyses of a novel Cbi-Ex4 compound for glucoregulation without eliciting nausea/emesis or competing with endogenous B12 transport in the musk shrew which both is capable of emesis and expresses HC, like the human, but unlike the mouse and rat. The compounds described herein also offer scope to investigate, through relatively simple experimentation, the role of CNS versus periphery in the function of GLP-1R agonists in animals and humans. As such they have significant potential as investigative research probes in addition to their clear potential as a new generation of therapeutics. Most notably, these highly innovative experiments will provide the necessary pre-clinical analyses for the B12- and/or Cbi-based conjugates of Ex4. Such studies will lead to significantly improved, clinically beneficial, second generation therapeutics for the treatment of T2DM without the most common nausea/malaise side effects of existing GLP- 1-based therapeutics, which will improve patient quality of life, patient compliance to therapy, and expand the population that can benefit from the amazing improved glycemic profile achieved with GLP-1R agonists.

项目概要 该 R01 应用的拟议研究重点是创建第二代胰高血糖素样肽- 基于 GLP-1 的药物保留了所有降血糖功能，但完全消除了 主要副作用为恶心、呕吐和不适。产生这种副作用以及吞咽功能减退 现有的 GLP-1R 激动剂由于中枢神经系统 (CNS) 的渗透性和在大脑中的直接作用而受到影响。 因此，我们试图创造脑外显率降低但具有全部效力的 GLP-1R 激动剂。 胰腺 GLP-1R 群体的药效学特征。我们新颖的初步数据令人信服 证明 GLP1-R 激动剂 Exendin-4 (Ex4) 的维生素 B12 (B12) 缀合物的能力，即 (B12- Ex4)，在小鼠和大鼠模型的葡萄糖耐量试验 (GTT) 中产生低血糖，但不产生 吞咽不足或恶心/不适。这种没有恶心/不适的血糖调节似乎是由于虚拟的 缺乏配体渗透到中枢神经系统，这一假设得到放射性标记 B12 研究的支持，表明 进入大脑的 B12 水平极低，以及荧光免疫组织化学分析 与中枢神经系统激活位点的天然 Ex4 相比，标记的 B12-Ex4。因此，该应用程序测试 以下具体目标是加强 B12-Ex4 作为第二代 T2DM 的临床前评估 治疗并检验以下假设：利用“B12 家族”的总治疗效果组合可以 通过将 Ex4 与 B12 片段（特别是 Cobinamide (Cbi)）缀合来增强，其靶向 Haptocorrin (HC)，一种仅在哺乳动物（包括人类）中发现的 Cbi 结合蛋白：[1] 表征生理、 介导 B12-Ex4 降血糖作用的行为和解剖机制，且不发生 使用瘦/血糖正常和肥胖/高血糖大鼠和小鼠模型观察吞咽不足和恶心/不适； [2] 对用于血糖调节的新型 Cbi-Ex4 化合物进行系统的体外和体内分析，无需 引起恶心/呕吐或与麝香鼩的内源性 B12 运输竞争，两者都有能力 呕吐并表达 HC，与人类相似，但与小鼠和大鼠不同。本文描述的化合物 还提供了通过相对简单的实验研究中枢神经系统与外周神经系统的作用的范围 GLP-1R 激动剂在动物和人类中的功能。因此，它们具有作为调查的巨大潜力 除了其作为新一代疗法的明显潜力之外，还对其进行了研究探索。最值得注意的是，这些 高度创新的实验将为基于 B12 和/或 Cbi 的药物提供必要的临床前分析 Ex4的缀合物。此类研究将带来显着改进、临床有益的第二代产品 治疗 T2DM 的疗法，没有现有 GLP-最常见的恶心/不适副作用 以 1 为基础的治疗方法，将改善患者的生活质量、患者对治疗的依从性，并扩大治疗范围 可以受益于 GLP-1R 激动剂所实现的令人惊叹的血糖曲线改善的人群。