Stabilization of Therapeutic Peptides by Non-Perturbative Chemical Modification

描述（由申请人提供）：2型糖尿病是一种特别使人衰弱的疾病，是世界上大部分人口的地方病。疾病管理中尚未解决的挑战是缺乏降低高血糖症的长期疗效和无法阻止进展。胰高血糖素样肽-1（GLP-1）是一种天然的肠道激素，为治疗该病提供了一个平台。肽通常具有有效的和选择性的生物活性，使得它们作为治疗剂是非常理想的，但是在医学中更广泛使用的主要障碍是有限的蛋白水解稳定性。GLP-1本身的高效力被注射后不到2分钟的半衰期抵消。我们的实验室一直在开发GLP 1类似物具有增强的蛋白水解稳定性：我们现在发现，设计用于提供大的稳定性增强的简单N-末端修饰在基于细胞的测定中保留了GLP-1的结合和活性。从历史上看，通过N-末端肽序列的化学修饰获得的稳定性仅以效力为代价获得，因此仍需要频繁注射以维持治疗益处。我们在塔夫茨大学的研究项目在G蛋白偶联受体（GPCR）的研究方面有经验，并在调节此类受体的肽配体的设计和合成方面产生了显着的创新。本提案的目的是证明我们的N-末端修饰肽在GLP-1受体（GLP-1 R）上的强结合、完全激动剂活性和蛋白酶稳定性，而不会改变N-末端序列。如果成功的话，这将是一种全新的肽稳定化方法。总之，这些研究将为蛋白酶稳定性差的其他肽的修饰设定基准并提供蓝图。在STTR机制的支持期结束时，这些研究应该为该平台技术的实施奠定基础，以用于可以以类似方式稳定的其他肽。

DESCRIPTION (provided by applicant): Type 2 diabetes is a particularly debilitating disease and is endemic for a large proportion of the world's population. The unmet challenges in disease management are the lack of long-term efficacy in reducing hyperglycemia and the inability to stop progression. Glucagon-like peptide-1 (GLP-1), a natural gut hormone, provides a platform for therapeutics to combat the disease. Peptides in general have potent and selective biological activities, making them highly desirable as therapeutics, but a major obstacle to more widespread use in medicine is limited proteolytic stability. The high potency of GLP-1 itself is nullified by a half-life of less than 2 min after injection. Our laboratory has been developing GLP 1 analogs with enhanced proteolytic stability for several years: we have now discovered that a simple N-terminal modification, designed to deliver large stability enhancements, preserves binding and activity of GLP-1 in cell- based assays. Historically, gains in stability via chemical modification of the N-terminal peptide sequence have been obtained only at the expense of potency, so that frequent injections would still be needed to maintain therapeutic benefit. Our research program at Tufts has experience in the study of G Protein-Coupled Receptors (GPCRs) and has produced notable innovations in the design and synthesis of peptide ligands that modulate such receptors. The goal of this proposal is to prove that strong binding at the GLP-1 receptor (GLP-1R), full agonist activity, and protease stability can be demonstrated for our N-terminal modified peptides, without otherwise altering the N- terminal sequences. If successful this would be a completely novel approach to peptide stabilization. Taken together, these studies will set a benchmark and provide a blueprint for the modification of other peptides that suffer from poor protease stability. At the end of the period of support by the STTR mechanism, these studies should set the stage for this platform technology to be implemented for other peptides that can be stabilized in a similar fashion.