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，是世界上很大一部分人口的地方病。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，为治疗这种疾病提供了一个平台。肽通常具有有效和选择性的生物活性，使其成为非常理想的治疗药物，但在医学上广泛应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分钟的半衰期所抵消。我们实验室一直在开发GLP

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.