Identification of novel viral entry factors and development of antiviral approaches

DEFENDER will address the need for innovative intervention strategies against viruses with epidemic potential, by adopting a comprehensive and integrative platform approach. DEFENDER's revolutionary Research and Innovation pipeline will focus on preventing virus entry through a host-directed bottom-up approach based on functional genetics in parallel to a top-down virus glycoprotein-centered approach. We will identify novel host dependency and restriction factors, including receptors and proteins involved in viral attachment and binding, endosomal uptake and virus genome uncoating, as targets for antiviral therapy. In parallel, we will use recombinant viral glycoproteins to identify broadly neutralizing nanobodies and novel epitopes for the AI-based design of next generation immunogens and the improvement of therapeutic antibodies. The host bottom-up functional genetic approach will be applied to Nipah, Lassa, Zika, Dengue, Yellow fever, and Chikungunya viruses. Host factors will be identified using a unique arrayed CRISPR perturbation platform, combined with advanced statistical and machine learning approaches and mathematical modelling, mechanistic experiments, and cutting-edge imaging techniques. In parallel, the virus top-down glycoprotein-centered approach will lead to the identification and structural characterization of broadly neutralizing nanobodies targeting conserved epitopes of the glycoproteins of Nipah and Lassa viruses in pre-fusion conformation. DEFENDER will deliver innovative antiviral candidates that induce target degradation, next generation immunogens, and a novel concept to improve the activity of therapeutic antibodies, with proof-of-concept preclinical evaluation in mice. It will define the most vulnerable virus-host interactions, to deliver a robust development pipeline for novel antivirals, therapeutic antibodies, and immunogens and increase antiviral options against a wide range of priority (re-) emerging viruses.