Deciphering how glycosylation protects peptides from proteolysis

描述（由申请人提供）：肽和蛋白质的糖基化通常会增加其对蛋白水解的抗性，但尚不清楚连接的糖如何赋予这种抗性。拟议的研究计划将创建一个程序，以确定如何通过连接糖或其他小有机分子来使肽和蛋白质抵抗蛋白水解。赋予蛋白水解抗性的一般结构基序将通过研究由糖与含有N-烷基氨基氧基氨基酸的肽的化学选择性连接合成的新糖肽阵列来发现。本研究的具体目的是：（1）合成新糖肽的组合阵列，（2）确定各种蛋白酶对新糖肽阵列成员的蛋白水解速率，以鉴定一般的保护性结构基序，以及（3）将这些基序引入生物活性肽，以增加其蛋白水解抗性，而不干扰其生物学功能。这项研究的长期目标是了解自然界如何利用糖基化来提供蛋白水解保护，并为新型肽和蛋白质药物的设计提供新的策略。由于其精致的生物活性和特异性，肽作为用于各种疾病状态的高选择性药物具有巨大的潜力。然而，这种潜力受到体内酶通常消化肽的速度的严重限制。了解和利用如何将糖连接到肽上以保护它们免受消化，将有助于创造新的强大肽药物。

DESCRIPTION (provided by applicant): The glycosylation of peptides and proteins commonly increases their resistance to proteolysis, but how the attached sugars confer this resistance is not well understood. The proposed research plan will create a program to determine how peptides and proteins can be made resistant to proteolysis by the attachment of sugars or other small organic molecules. General structural motifs that confer proteolytic resistance will be discovered by studying arrays of neoglycopeptides synthesized by chemoselective attachment of sugars to peptides containing N-alkylaminooxy amino acids. The specific aims of the research are: (1) synthesizing a combinatorial array of neoglycopeptides, (2) determining the rates of proteolysis of the members of the neoglycopeptide array by a variety of proteases in order to identify general, protective structural motifs, and (3) introducing these motifs to bioactive peptides to increase their proteolytic resistance without disturbing their biological function. The long term goal of this research is to understand how nature uses glycosylation to provide proteolytic protection and to provide new strategies for the design of novel peptide and protein pharmaceuticals. Because of their exquisite biological activity and specificity, peptides have tremendous potential as highly selective pharmaceuticals for a wide variety of disease states. However, that potential is severely limited by how fast peptides are typically digested by enzymes in the body. Understanding and using how attaching sugars to peptides protects them from digestion would enable the creation of new classes of powerful peptide pharmaceuticals.