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"孪生流行病"，迫切需要找到 有效的新药物治疗诱导体重减轻。内源性葡萄糖调节因子的稳定衍生物 激素，胰高血糖素样肽-1（GLP 1）在临床上用于治疗T2D，但也引起了极大的兴趣 作为一种新兴的治疗肥胖的方法。另一种密切相关的葡萄糖调节激素，葡萄糖依赖性 最近有报道称，促胰岛素肽（GIP）可进一步增强GLP 1诱导的体重减轻 基于药物。然而，为了使GIP在临床上有用，需要对这种肽进行修饰以防止快速的免疫反应。 酶降解和延迟从血流中清除。申请人（Velum，Inc.）有机会接触 一种受专利保护的新策略，使GIP完全抵抗其主要的氨基- 末端酶促裂解。这可以通过将功能良好的装饰物附加到 肽的第一个氨基酸，以及添加脂质侧链，进一步延迟肽 消除/失活。在目前的第二阶段申请中，申请人建议采用这一战略， 目标是确定一个领先的GIP衍生物和“备份”，持有治疗的承诺。结束时 在项目期间，将推进一到三种化合物，以测试人体安全性并实现IND申请。 与塔夫茨大学合作，将追求两个具体目标。从原型稳定GIP开始 类似物，目的1是通过引入 在GIP肽中的可行残基处的替代氨基末端装饰和脂质侧链。共 因此将产生83个新的后续分子。将测试这些药物的激动剂活性/受体效价 通过受体信号传导测定。将进一步测试20种最具活性的衍生物的体外酶稳定性， 包括对DPP 4以及胰蛋白酶和脑啡肽酶的抗性。在目标2中，六种具有最高效力的类似物 并选择稳定性用于研究s.c.注射小鼠。一个敏感 生物测定将用于监测为该项目开发的肽活性， 检测，而不考虑结构修改。此外，药物诱导的体重减轻将在 饮食诱导的肥胖小鼠。作为实验范例，GIP类似物将每天共注射一次， 三个星期的时间与最新一代的GLP 1为基础的药物，从而使检测协同 对体重减轻和肥胖相关高血糖症的影响。目标是提名一个主要的GIP类似物和两个 IND使能研究的备用化合物，进一步开发一种伴随药物， GLP 1诱导的肥胖症治疗。

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.