Mapping natural glycan interactomes: investigating protein-glycan interactions in natural systems

The National Institute of General Medical Sciences awarded Emory University $430,375 in a Project Grant (Assistance Listing 93.859, Biomedical Research and Research Training) on August 1, 2026, to support systematic studies of natural glycans and their interactomes through innovative methodologies for protein-glycan interaction research.

The work develops and applies advanced chemistry tools—including the Oxidative Release of Natural Glycans (ORNG) method and DNA-encoded glycan libraries as next-generation microarray platforms—to overcome technical barriers in glycoscience. The ORNG method enables scalable, cost-effective extraction of diverse natural glycans from biological sources at milligram-to-gram scales, addressing the field's critical shortage of complex glycans for functional studies. The research program expands the available natural glycan repertoire by targeting low-abundance glycans with potentially significant biological functions and advances preparative separation techniques to support downstream applications in glycosylation engineering, glycopeptide and glycoprotein synthesis, and therapeutic development.

Emory University's Office of Sponsored Programs administers the award. Place of performance is Atlanta, Georgia. The period of performance runs from August 1, 2026, through May 31, 2031. The program supports basic research that increases understanding of biological processes and lays the foundation for advances in disease diagnosis, treatment, and prevention.

Abstract

Glycoconjugates, including glycoproteins, glycolipids, and glycosaminoglycans, are fundamental to cellular communication, immune responses, and molecular recognition. The glycome's complexity and dynamic nature underscore its importance, yet the field of glycoscience lags behind other areas due to the structural complexity of glycans and limited analytical tools. In the last two decades, we have dedicated our effort to developing novel chemistry and tools to remove technical barriers in glycoscience and to facilitate the study of protein-glycan interactions. This proposal seeks to address these challenges by leveraging and expanding innovative methodologies developed in our laboratory, including the oxidative release of natural glycans (orng) and DNA-coded glycan libraries as next-generation glycan microarrays. The orng method has revolutionized glycan extraction, enabling scalable and cost-effective production of diverse natural glycans from biological sources. This innovation addresses critical bottlenecks in glycoscience, such as the limited availability of complex glycans for functional studies. Building on this success, our work has advanced preparative glycan separation techniques, allowing high-purity isolation of glycans at milligram-to-gram scales. These developments are crucial to many groundbreaking applications in glycoscience, including glycosylation engineering and the synthesis of glycopeptides and glycoproteins, which are pivotal for studying glycan functions and developing therapeutics. Looking ahead, our research program aims to deepen the understanding of glycan-mediated processes through systematic studies of natural glycans and their interactomes. We will expand our natural glycan repertoire by targeting low-abundance glycans with potentially significant biological functions. This includes developing advanced enrichment strategies for glycan subclasses such as sialylated, phosphorylated, and sulfated glycans, which are critical in biological pathways but remain challenging to isolate and synthesize. Additionally, we will employ these glycans as substrates for enzymatic synthesis, generating structurally diverse libraries that will support functional and therapeutic studies. A cornerstone of our future work is the application of DNA-coded glycan libraries to investigate intact cell surface protein-glycan interactomes. Traditional glycan microarrays, while transformative for studying glycan-protein interactions, are limited in their compatibility with large and complex biological systems. Our solution-based approach integrates DNA sequencing technologies, enabling high-throughput, scalable analyses of glycan binding properties on cell surfaces. This technology will be applied to a range of cell lines, including cancer cells, to uncover glycan ligands that can serve as biomarkers for early diagnosis, prognosis evaluation, and therapeutic development. By addressing critical challenges in glycan isolation, enrichment, and functional analysis, our research will advance the field of glycoscience, fostering discoveries in basic science and translational applications. This comprehensive approach is poised to uncover novel insights into glycoscience and its implications for health and disease. 1