FOR 2327:  VIROCARB: Glycans Controlling Non-Enveloped Virus Infections

• Subject Area: Medicine ; Biology ; Chemistry
• Term: from 2016 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 269564371

The overall goal of the research unit VIROCARB is to define the role of glycans in viral infections. Glycans are carbohydrate structures that decorate all cell surfaces and most secreted proteins of higher evolved species. They are attached to either proteins or membrane components such as lipids, and they act as ligands for many glycan-binding host proteins. Pathogens such as viruses frequently engage such glycans, thereby establishing a first contact that can then be used to mount a productive infection.VIROCARB will focus on three families of non-enveloped viruses: Noroviruses, Polyomaviruses and Papillomaviruses. All three viruses include human pathogens, and in all three cases glycans play critical roles in cell attachment and determining host range and tropism. We will first define the parameters that, at the atomic level, guide glycan-binding for members of each of these virus families, and, subsequently, use this knowledge to develop novel compounds with inhibitory and thus antiviral activities. Moreover, a detailed understanding of glycan receptor interactions and the comparison with antibody interactions will also be used to uncover strategies that allow viruses to switch receptor specificities and alter their host tropism. Such an ambitious undertaking is only possible by drawing on the unique expertise from each research unit group in this area, such as structural analyses using crystallography, interaction measurements using NMR spectroscopy, and cell- and animal-based studies of glycan-dependent viral infections. These studies are being complemented with expertise in techniques such as chemical synthesis to generate novel ligands, mass spectrometry to characterize the composition of virus particles, and membrane biophysics to define and analyze the parameters that enable virus entry. The research unit has assembled this expertise and is therefore poised to significantly advance an understanding of virus biology.Key objectives for the second funding period are: (i) Characterize the evolution of glycan binding sites in closely related viruses, and correlate this with host tropism, (ii) Apply recently-developed tools for mechanistic studies, diagnostics and inhibition of infection, including glycomimetics and antibody fragments, (iii) Investigate allosteric effects and conformational changes in viruses that are triggered by binding to glycans, antibodies or fragments thereof, and proteinaceous receptors, (iv) Define the influence of plasma membrane lipid composition and geometrical receptor constraints on virus attachment and entry, and (v) Formulate and test glycomimetics as anti-viral lead compounds.

• DFG Programme: Research Units

Projects

• Assembling glyco-functionalized surfaces and membranes based on precision glycomacromolecules to study viral adhesion and inhibition (Applicant Hartmann, Laura )
• Coordination Funds (Applicant Stehle, Thilo )
• Differential roles of two types of Glycans for cell attachment and entry of Merkel cell polyomavirus (Applicant Stehle, Thilo )
• Glycans attaching to Noroviruses - Allosteric Cross talk meets post translational modification (Applicant Peters, Thomas )
• Glycosaminoglycan-papillomavirus interactions: From structure to function and inhibition (Applicant Schelhaas, Mario )
• Neutralizing the human Norovirus Histo-Blood Group Antigen Binding Pocket (Applicant Hansman, Grant )
• New roles of Glycans in Norovirus infection: From structure to function to inhibition (Applicant Taube, Stefan )
• Receptor Binding and Inhibition of Glycan-binding Polyomaviruses (Applicant Stehle, Thilo )
• Structural Dynamics upon directed Virus Glycan interaction (Applicant Uetrecht, Charlotte )
• Valency and Geometry of multivalent Glycolipid binding as cellular targeting mechnaism in viral infection (Applicant Ewers, Helge )

• Spokesperson: Professor Dr. Thilo Stehle