Deciphering how glycosylation protects peptides from proteolysis

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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.