Preparing for disease X, the next pathogenic respiratory viruses: the development of cross-reactive nanobodies for diagnosis, prophylaxis and treatment of coronavirus infections.

We will address the urgent and unmet need within the biomedical community for effective agents to combat the existing threat from coronaviruses and to be prepared for those that will arise in the future. We will also deliver a pipeline that will be applicable to other high threat respiratory viruses (Disease X). We propose to build a nanobody screening strategy that targets cross-reactivity from which we anticipate identifying (pan)-coronavirus binders. The pipeline will combine nanobody technology, structural biology and virology making use of the Diamond synchrotron at Harwell for X-ray data collection and the CL3 facilities in Oxford and Liverpool for handling live viruses. Together the results will enable the structure-activity relationships of anti-coronavirus nanobodies to be determined providing information that will guide sequence changes to increase nanobody binding and counter the effects of virus escape mutants or natural variants on virus detection and neutralisation. The demonstration of in vivo potency to SARS-CoV-2 and other than coronaviruses(cross therapeutic) is a key aim of the proposal and we will test any new potent neutralising nanobodies in an appropriate disease model.