Activated Sugars, Oligosaccharides and Glycans for Antiviral Research

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SUMMARY The goal of this project is to develop novel methods to produce sugar building blocks, oligosaccharides, and glycans needed to support and grow R&D related to viral glycobiology at large scale and reasonable prices. This technology will support researchers studying viral pathology, analyses of viral binding and interactions with hosts, studies to develop novel antiviral therapeutics and vaccines, and others. Glycobiology is important in a number of ways for viral research. Viral surface proteins are often heavily glycosylated to both avoid recognition by the host cell and, in some cases, interact with host receptors. For example, the spike protein glycosylation of the SARS-CoV-2 virus is usually the extension of an N-linked core pentasaccharide compound, composed of a stem of chitobiose followed by mannoses to form two antennary complexes. Understanding glycosylation of viral spike proteins and their potential epitope masking is of fundamental importance for vaccine research. Receptors recognized by many viruses are glycosylated proteins as well. SARS-CoV-2 and others uses angiotensin-converting enzyme 2, (ACE2) as its receptor, and other b-coronaviruses, utilize sialic acid residues on cellular glycoproteins as receptors. Glycans are currently being studied as vaccines against viruses (Dengue, Hepatitis C), parasites (Plasmodium) and fungi (Candida). Human milk oligosaccharides (HMOs) have been shown to reduce the possibility of infections due to interference with adhesion of pathogenic bacteria and potentially viruses. Galectins have been shown have pro- or anti-viral properties and play important role in innate immunity. Finally, some galectin inhibitors may block HIV infection of T cells. Oligosaccharides are currently isolated from nature or synthesized at extremely low yield via a complex set of protection and deprotection steps. Oligosaccharides and the activated sugar building blocks needed to build them enzymatically are needed in larger quantities to support and spawn additional research in this important field. In the Feasibility study we successfully demonstrated the development of a set of novel enzymes to produce a wide range of key activated sugar building blocks required to build important oligosaccharides. We then demonstrated the use of these activated sugars to extend model oligosaccharide chains. In the Phase II work, we will increase the scale of production of all of these activated sugars, extend the system to produce additional activated sugars needed, and make a number of key oligosaccharides important to viral biology research. Products made during the Phase II Research will be distributed to investigators and in Phase III products will be commercialized as part of our research reagent catalog or by carrying out custom synthesis of oligosaccharides for third parties.