Deciphering how glycosylation protects peptides from proteolysis

描述(申请人提供)：多肽和蛋白质的糖基化通常会增加它们对蛋白质分解的抵抗力，但结合的糖如何赋予这种抵抗力还不是很清楚。拟议的研究计划将创建一个项目，以确定多肽和蛋白质如何通过附着糖或其他有机小分子来抵抗蛋白质分解。通过研究含有N-烷基氨基氧基氨基酸的多肽与糖的化学选择性结合而合成的一系列新糖肽，将发现赋予蛋白水解性抗性的一般结构基序。这项研究的具体目的是：(1)合成新糖肽的组合阵列，(2)测定新糖肽阵列成员被各种蛋白酶的蛋白分解速率，以确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多肽，以在不干扰其生物学功能的情况下增加其蛋白分解抗性。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质降解保护，并为设计新型多肽和蛋白质药物提供新的策略。由于其精致的生物活性和特异性，多肽作为治疗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消化多肽的速度的严重限制。了解和使用将糖结合到多肽上如何防止它们被消化，将能够创造出新的强大的多肽药物。

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.