A GIP Companion Drug for Enhancing Metabolic Benefits of Long-Acting GLP-1

一种增强长效 GLP-1 代谢功效的 GIP 伴侣药物

基本信息

批准号：
10626143
负责人：
Martin Beinborn
金额：
$ 47.83万
依托单位：
VELUM, INC.
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10626143
关键词：
Acylation Adipocytes Advanced Development Agonist Amino Acids Animal Model Animals Biological Assay Biological Availability Blood Blood Glucose Body Weight decreased C57BL/6 Mouse COVID-19 Cardiovascular Diseases Cell physiology Cells Chemicals Clinic Clinical Clinical Trials Collaborations Companions Detection Development Diabetes Mellitus Dipeptidyl Peptidases Drug Targeting Duodenum Engineering Enteroendocrine Cell Enzyme Stability Enzyme Tests Expenditure Fatty Acids Gastric Inhibitory Polypeptide Generations Glucose Goals Half-Life Health Health Care Costs Hormones Human Hyperglycemia In Vitro Industry Injections Kidney Lead Legal patent Ligands Lipids Metabolic Minor Modification Mucous Membrane Mus N-terminal Neprilysin Neurodegenerative Disorders Non-Insulin-Dependent Diabetes Mellitus Obesity Obesity Epidemic Osteoporosis Overweight Pathway interactions Patients Peptide Hydrolases Peptides Pharmaceutical Preparations Pharmacotherapy Phase Physiological Physiology Population Receptor Signaling Regulation Reporting Resistance Safety Side Stream Structure of beta Cell of islet Technology Testing Therapeutic Trypsin Twin Multiple Birth United States Food and Drug Administration Universities Weight-Loss Drugs analog comorbidity diet-induced obesity disorder risk drug clearance drug discovery follow-up glucagon-like peptide 1 improved in vivo insulin secretion interest liraglutide neglect novel novel strategies novel therapeutics obese patients obesity treatment pancreatic secretory trypsin inhibitor I peptide analog pharmacologic phase 1 study phase 2 study polypeptide prevent prototype public health relevance receptor safety assessment safety testing side effect synergism therapeutic candidate translational pipeline

Acylation Adipocytes Advanced Development Agonist Amino Acids Animal Model Animals Biological Assay Biological Availability Blood Blood Glucose Body Weight decreased C57BL/6 Mouse COVID-19 Cardiovascular Diseases Cell physiology Cells Chemicals Clinic Clinical Clinical Trials Collaborations Companions Detection Development Diabetes Mellitus Dipeptidyl Peptidases Drug Targeting Duodenum Engineering Enteroendocrine Cell Enzyme Stability Enzyme Tests Expenditure Fatty Acids Gastric Inhibitory Polypeptide Generations Glucose Goals Half-Life Health Health Care Costs Hormones Human Hyperglycemia In Vitro Industry Injections Kidney Lead Legal patent Ligands Lipids Metabolic Minor Modification Mucous Membrane Mus N-terminal Neprilysin Neurodegenerative Disorders Non-Insulin-Dependent Diabetes Mellitus Obesity Obesity Epidemic Osteoporosis Overweight Pathway interactions Patients Peptide Hydrolases Peptides Pharmaceutical Preparations Pharmacotherapy Phase Physiological Physiology Population Receptor Signaling Regulation Reporting Resistance Safety Side Stream Structure of beta Cell of islet Technology Testing Therapeutic Trypsin Twin Multiple Birth United States Food and Drug Administration Universities Weight-Loss Drugs analog comorbidity diet-induced obesity disorder risk drug clearance drug discovery follow-up glucagon-like peptide 1 improved in vivo insulin secretion interest liraglutide neglect novel novel strategies novel therapeutics obese patients obesity treatment pancreatic secretory trypsin inhibitor I peptide analog pharmacologic phase 1 study phase 2 study polypeptide prevent prototype public health relevance receptor safety assessment safety testing side effect synergism therapeutic candidate translational pipeline

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项目摘要

Project Summary There is a world-wide “twin epidemic” of obesity and Type 2 Diabetes (T2D), with an urgent need to find effective new drug treatments for inducing weight loss. Stable derivatives of the endogenous glucoregulatory hormone, glucagon-like peptide-1 (GLP1) are in clinical use for the treatment of T2D but are also of great interest as an emerging treatment of obesity. Another closely related glucoregulatory hormone, glucose-dependent insulinotropic peptide (GIP) has been recently reported to further enhance the weight loss induced by GLP1 based medications. However, for GIP to be clinically useful, this peptide needs to be modified to prevent rapid enzymatic degradation and to delay clearance from the blood stream. The applicants (Velum, Inc.) have access to a patent-protected novel strategy to make GIP fully resistant to its main inactivation mechanism of amino- terminal enzymatic cleavage. This can be achieved by attaching functionally well-tolerated decorations to the peptide’s first amino acid, together with adding a lipid side chain that further delays peptide elimination/inactivation. In the current phase II application, the applicants propose to apply this strategy with the goal of identifying a lead GIP derivative and “backups” that hold therapeutic promise. At the end of the project period, one to three compounds will be advanced to test safety in humans and enable IND filings. In collaboration with Tufts University, two Specific Aims will be pursued. Starting with a prototype stable GIP analogue that has already been engineered, Aim 1 is to further improve on this molecule by introducing alternative amino-terminal decorations and lipid side chains at feasible residues in the GIP peptide. A total of 83 new follow-up molecules will thus be generated. These will be tested for agonist activity/receptor potency by receptor signaling assay. Twenty most active derivatives will be further tested for enzyme stability in vitro, including resistance to DPP4 as well as to trypsin and neprilysin. In Aim 2, six analogues with highest potency and stability will be selected for studying half-life in the blood stream following s.c. injection in mice. A sensitive bioassay will be used to monitor peptide activity that has been developed for this project to enable compound detection regardless of structural modifications. Furthermore, drug-induced weight loss will be quantified in mice with diet-induced obesity. As the experimental paradigm, GIP analogues will be co-injected daily over a three-week period together with a latest generation GLP1-based drug, thus enabling the detection of synergistic effects on weight loss and obesity-related hyperglycemia. The goal is to nominate a lead GIP analogue and two backup compounds for IND-enabling studies, toward further development of a companion drug that amplifies GLP1-induced treatment of obesity.

项目摘要肥胖和2型糖尿病（T2D）有一个世界范围内的“双胞胎流行”，迫切需要找到有效的新药物治疗可诱导体重减轻。内源性糖调节的稳定衍生物马酮，胰高血糖素样肽-1（GLP1）用于治疗T2D，但也引起了人们的极大兴趣作为肥胖的新兴治疗方法。另一个密切相关的糖调节马酮，葡萄糖依赖性最近据报道，胰岛素胡椒（GIP）进一步增强了GLP1诱导的体重减轻基于药物。但是，要使GIP在临床上有用，需要修改该肽以防止快速酶促降解并延迟血流清除。申请人（Velum，Inc。）已访问采取专利保护的新型策略，使GIP完全抵抗其氨基的主要失活机制末端酶裂解。这可以通过将功能良好的装饰连接到肽的第一个氨基酸，加上添加脂质侧链，进一步延迟了胡椒粉消除/失活。在当前II阶段应用程序中，应用程序提案将此策略应用于确定具有治疗诺言的铅GIP衍生物和“备用”的目标。在项目期，将提出一种一到三种化合物来测试人类的安全并启用IND归档。与塔夫茨大学合作，将实现两个具体的目标。从原型稳定的GIP开始已经设计过的类似物，目标1是通过引入该分子进一步改善该分子在GIP胡椒中可行保留的替代氨基末端装饰和脂质侧链。总共因此，将产生83个新的随访分子。这些将测试激动剂活性/受体效力通过接收器信号测定。将进一步测试二十种最活跃的衍生物，以实现体外酶稳定性，包括对DPP4以及胰蛋白酶和Neprilysin的抗性。在AIM 2中，六个具有最高效力的类似物并将选择稳定性以在S.C.之后的血流中研究半衰期。小鼠注射。敏感生物测定将用于监视为该项目开发的肽活动以启用化合物检测无论结构修改如何。此外，药物诱导的减肥将在饮食引起的肥胖症的小鼠。作为实验范式，GIP类似物每天都会在三周的时期以及最新一代的基于GLP1的药物，从而可以检测协同作用对体重减轻和肥胖相关的高血糖的影响。目标是提名铅GIP类似物和两个用于辅助研究的备份化合物，以进一步开发伴随药物以放大器 GLP1诱导的物体处理。