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: 10357951
• 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/10357951
• 关键词: Acute; Agonist; Amaze; Anatomy; Animals; Attention; Automobile Driving; Behavior; Behavioral; Beta Cell; Binding; Binding Proteins; Blood; Blood Glucose; Body Weight; Body Weight decreased; Brain; Brain Stem; Cachexia; Carrier Proteins; Cell Line; Chemicals; Chronic; Clinical; Complex; 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; Health Care Costs; Hormones; Human; Hyperglycemia; Hypoglycemia; Hypothalamic structure; In Vitro; Incidence; Insulin; Intake; Intestines; Intracellular Transport; Intrinsic factor; Kaolin; Life; Ligands; Malaise; Mammals; Mediating; Mediator of activation protein; Medical; Medical Economics; Modeling; Mus; Nausea; Nausea and Vomiting; Neuraxis; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Pancreas; Patients; Pattern; Penetrance; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Pharmacopoeias; Pharmacotherapy; Physiological; Population; Prognosis; Public Health; Publishing; Quality of life; Rattus; Reporting; Research; Rodent Model; Role; Shrews; Sick Role; Site; Testing; Therapeutic; Therapeutic Effect; Thinness; Tissues; Transcobalamins; Vagus nerve structure; Vitamin B 12; Vomiting; analog; base; cobinamide; comorbidity; compliance behavior; design; diet-induced obesity; economic cost; exenatide; experience; experimental study; glucagon-like peptide 1; glycemic control; improved; in vivo; incretin hormone; inhibitor; innovation; insulin secretion; mouse model; novel; pancreatic juice; pre-clinical; pre-clinical assessment; reduced food intake; side effect; subcutaneous; therapeutic evaluation; 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 这项R01应用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，保留了所有的降血糖曲线，但完全消除了 恶心、呕吐和不适的主要副作用。这样的副作用，以及低吞咽症，就会产生。 由现有的GLP-1R激动剂由于中枢神经系统(CNS)的穿透和在大脑中的直接作用而产生的。 因此，我们试图创造GLP-1R激动剂，其大脑外显率降低，但具有完全的效力 胰腺GLP-1R人群的药效学概况。我们新奇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)结合物的能力，即(B12- EX4)，在小鼠和大鼠的葡萄糖耐量试验(GTT)中产生低血糖，而不产生 吞食不足或恶心/不适。这种没有恶心/不适的血糖调节似乎是由于一种虚拟的 缺乏配体进入中枢神经系统，这一假说得到了放射性标记的B12研究的支持 极低水平的B12进入大脑，以及免疫组织化学分析荧光- 在中枢神经系统激活部位标记B12-EX4与天然EX4的比较。因此，此应用程序测试 以下具体目标是加强B12-EX4作为第二代T2 DM的临床前评估 治疗并检验这样一个假设，即利用B12家族的全部治疗效果组合可以 通过将EX4结合到B12的一段片段上，特别是针对Haptocorrin的可比酰胺(CBI)来增强 (HC)，一种只在哺乳动物中发现的CBI结合蛋白，包括人类：[1]表征了生理上的， B12-EX4降血糖作用的行为学和解剖学机制 使用瘦/正血糖和肥胖/高血糖的大鼠和小鼠模型，出现吞噬减少和恶心/不适； [2]对一种新型的CBI-EX4糖调节化合物进行了系统的体外和体内分析 在麝鼠体内引起恶心/呕吐或与内源性B12运输竞争，两者都有能力 和人类一样表达HC，但不同于小鼠和大鼠。这里描述的化合物 还提供了通过相对简单的实验来研究中枢神经系统与外周神经系统在 GLP-1R激动剂在动物和人类中的作用。因此，他们作为调查人员具有巨大的潜力 除了它们作为新一代治疗学的明确潜力外，研究还进行了探索。最值得注意的是，这些 高度创新的实验将为B12和/或CBI提供必要的临床前分析 EX4的共轭。这样的研究将导致显著改善的、临床上有益的第二代 治疗没有现有GLP最常见的恶心/不适副作用的T2 DM- 以1为基础的治疗，这将提高患者的生活质量，患者对治疗的依从性，并扩大 可以从GLP-1R激动剂实现的令人惊叹的血糖改善中受益的人群。