MOLECULAR STRATEGIES AGAINST VIRAL ENTRY AND GLYCAN SHIELDING

The SHIELD consortium targets two closely related steps in the viral replication cycle that are, as yet, difficult to study and to exploit for therapeutic interventions: 1) Virion glycosylation in the context of uptake, maturation and viral immunity. 2) Virion dynamics of entry into cells, where the plasticity of the involved proteins and their glycosylation status have key roles. The viruses studied in SHIELD are from the genera of flavivirus (DENV, WNV, YFV, Zika), mammarenaviruses (LASV) and henipaviruses (Hendra, Nipah). We bring a broad spectrum of methodical expertise to understand and exploit the interrelated processes of viral glycosylation and viral dynamics. Molecular simulations will enable the identification of cryptic pockets in viral proteins that form during the entry process, and the design of inhibitory ligands that bind to such pockets. Theoretical methods will be used to identify ligands for glycosylated viral proteins. This is intertwined with cryo-EM and nano-resolution optical microscopy which enable a detailed analysis of these events, their sensitivity to biological and chemical interference, and will allow a rational optimization of specificity and affinity. Novel chemical and biological entities (NCEs, NBEs) as tool compounds and potential starting points for drug development are obtained by targeted chemical synthesis, X-ray fragment screening, and nanobody library screens. Additionally, we study biological processes and the influence of interactions in systems of increasing complexity, which range from biochemical in-vitro to cellular assays and in vivo animal models. As the 'glycan shield' in Lassa/Hendra/Nipah plays a major role in immune evasion, we explore the immunological effects of an interference with protein glycosylation leading to novel starting point towards the development of effective and robust vaccines. In conclusion, SHIELD delivers a deeper understanding, and molecular tools to prepare the EU for future pandemic events.