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.

项目摘要 R 01申请的拟议研究重点是创造第二代胰高血糖素样肽- 1（GLP-1）为基础的药物，保留所有的血糖降低，但完全消除 恶心、呕吐和不适等主要副作用。这种副作用，沿着食欲减退， 由于中枢神经系统（CNS）的抑制和在大脑中的直接作用，受现有GLP-1 R激动剂影响。 因此，我们试图创建具有降低的脑代谢率但具有完全有效的GLP-1 R激动剂。 胰腺GLP-1 R人群的药效学特征。我们新的初步数据令人信服地 证明GLP 1-R激动剂毒蜥外泌肽-4（Ex 4）的维生素B12（B12）缀合物，即（B12- Ex 4），以在小鼠和大鼠模型中的葡萄糖耐量试验（GTT）中产生低血糖，而不产生 食欲减退或恶心/不适。这种无恶心/不适的血糖调节似乎是由于 缺乏配体转运进入CNS，放射性标记B12研究支持这一假设， 极低水平的B12进入大脑，以及免疫组织化学分析的荧光- 标记的B12-Ex 4与天然Ex 4在CNS活化位点的比较。因此，此应用程序测试 以下具体目标是加强B12-Ex 4作为第二代T2 DM的临床前评估 治疗和测试的假设，总的投资组合的治疗效果，利用'B12家庭'， 通过Ex 4与B12的片段，特别是靶向结合咕蛋白的cobinamide（Cbi）的缀合来增强 (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-Ex 4降血糖作用的行为和解剖学机制， 使用瘦/正常血糖和肥胖/高血糖大鼠和小鼠模型的食欲减退和恶心/不适; [2]对用于葡萄糖调节的新型Cbi-Ex 4化合物进行系统的体外和体内分析， 引起恶心/呕吐或与麝香鼩内源性B12转运竞争， 与人类一样，表达HC，但与小鼠和大鼠不同。本文所述的化合物 还提供了范围，调查，通过相对简单的实验，中枢神经系统与外周的作用， GLP-1 R激动剂在动物和人体中的功能。因此，它们具有作为调查工具的巨大潜力。 除了作为新一代治疗药物的明确潜力之外，最值得注意的是，这些 高度创新的实验将为基于B12和/或Cbi的治疗提供必要的临床前分析。 Ex 4的缀合物。这些研究将导致显着改善，临床上有益的，第二代 用于治疗T2 DM的治疗剂，无现有GLP的最常见恶心/不适副作用- 1-基于治疗，这将提高患者的生活质量，患者对治疗的依从性，并扩大 GLP-1 R激动剂可显著改善血糖特征，