Glycoproteins via Chemoselective Ligation of Proteins and Glycans

Washington State University, Pullman WA

Investigators

Abstract

The Chemical Synthesis Program of the Chemistry Division supports this project by Professor Philip Garner. Professor Garner is a faculty member in the Department of Chemistry at Washington State University. He is developing new methodology for the synthesis of glycoproteins, which are found widely in eukaryotic cells and play important roles cell-cell signaling, immune response, and neuronal development. The study of glycoproteins has been limited by their inaccessibility. This project blends chemical and biological approaches to develop a new suite of tools for the conjugation of glycans to both unprotected peptides and ultimately proteins. Because of its interdisciplinary nature, it is well suited for the education of scientists at all levels. Professor Garner's group is also well positioned to provide the highest level of education and training for students underrepresented in science. Outreach activities involving local community college students are also part of the funded project.   The project develops methodology for the convergent synthesis of glycoproteins, specifically focusing on reactions that could be used for the assembly of glycophosphatidylinositol (GPI)-conjugated proteins and N-glycoproteins. Both of these posttranslational protein modifications are found widely in eukaryotic cells and play important roles in a variety of biological processes. The study of glycosylated proteins has been limited by the difficulty in obtaining these substances in homogeneous form. Currently available chemoenzymatic approaches either do not produce native structures (GPI-conjugated proteins) or are not general (N-glycoproteins). This project is developing a solution that is based on the Cu(II)-mediated coupling of protein thioacids and glycan amines. These Cu(II)-mediated couplings are distinguished from other ligation reactions by their enhanced rates and chemoselectivities, which appear to be a function of a unique reaction mechanism. The approach is novel and could, in theory, be applied to any GPI- and N-glycoprotein. GPI-proteins are expressed on the surface of neurons, fibroblasts, endothelial cells and many other cell types. The project trains both graduate and undergraduate students in organic synthesis and its application to biological molecules. This activity benefits our society by preparing a new generation of students for careers in either academia or the pharmaceutical/biotech sectors. The project addresses the currently limited interaction of students and faculty at local community colleges with scientists actively engaged in research at the university level through a planned symposium.