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

项目摘要 肥胖和2型糖尿病(T2D)是世界范围内的双胞胎流行病，迫切需要找到 有效的减肥新药疗法。内源性糖调节的稳定衍生物 激素，高血糖素样多肽-1(GLP1)在临床上用于治疗T2D，但也引起了人们的极大兴趣 作为一种新兴的肥胖症治疗方法。另一种密切相关的糖调节激素--葡萄糖依赖型 最近有报道称，促胰岛素肽(GIP)可进一步增强GLP1引起的体重减轻 以药物为基础。然而，为了使GIP在临床上有用，需要对这种多肽进行修饰，以防止快速 酶促降解，延缓血液清除。申请者(Velum，Inc.)有权访问 一种受专利保护的新策略，使GIP完全抵抗其主要的氨基- 末端酶裂解。这可以通过将功能上容错良好的装饰附加到 多肽的第一个氨基酸，加上进一步延迟多肽的脂质侧链 消除/失活。在目前的第二阶段申请中，申请者建议将这一战略应用于 目标是确定具有治疗前景的主要GIP衍生品和“备份”。在结束时， 在项目期间，将提前一到三种化合物来测试人体安全性，并使IND备案。 将与塔夫茨大学合作，实现两个具体目标。从一个稳定的GIP原型开始 已经被设计的类似物，目标1是通过引入 GIP多肽中可行残基的替代氨基末端修饰和脂类侧链。总计 因此，将产生83个新的后续分子。这些将被测试激动剂活性/受体效力。 通过受体信号转导分析。20个最活跃的衍生物将在体外进一步测试酶的稳定性， 包括对DPP4的抗性以及对胰蛋白酶和奈普利辛的抗性。在目标2中，六个具有最高效力的类似物 稳定性将被选择用于研究S.C.后的血流半衰期。给小鼠注射。一个敏感的人 生物测定法将用于监测为该项目开发的多肽活性，以使化合物 检测，而不考虑结构修改。此外，药物导致的体重减轻将在 饮食诱导肥胖的小鼠。作为实验范例，GIP类似物将在一年内每天联合注射 与最新一代基于GLP1的药物一起使用三周，从而能够检测到协同作用 对减肥和肥胖相关的高血糖的影响。目标是提名一名首席GIP模拟人员和两名 支持IND研究的备用化合物，进一步开发一种可放大的配套药物 GLP1诱导的肥胖治疗。

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.