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Title: Antibody-guided discovery of potent small-molecule fusion inhibitors of influenza virus

Maria van Dongen

Johnson & Johnson, Belgium

Biography

Maria was appointed Director, Discovery Sciences in Janssen Research & Development in 2016, to lead multiple early drug discovery programs, and where she presently leads the Discovery Sciences’ External Innovation team. Before her current role, she served as member of the Jansen Prevention Management Team, Head of Preventive Interventions and led global teams working to deliver preclinical proof of concept for innovative products, focusing on small molecule drugs and B-cell vaccines. During her tenure, she brought distinguished small molecule discovery expertise to the specific needs related to preventive interventions and played a pivotal role in research that resulted in innovative antibody-guided drug discovery. Prior to joining Janssen, Maria held scientific positions in pharmaceutical research organizations, including Abbott, Solvay Pharmaceuticals, Biovitrum, Pharmacia Corporation and Pharmacia & Upjohn. She holds a Ph.D. in biophysical chemistry from the Radboud University Nijmegen, the Netherlands.

Abstract

Influenza therapeutics with new targets and mechanisms of action are urgently needed to combat potential new pandemics, emerging viruses, and constantly mutating circulating strains. We report here on discovery and structural characterization of potent peptidic and non-peptidic small-molecule inhibitors against influenza hemagglutinin (HA). Guided by structural knowledge of the interactions and mechanism of anti-stem broadly neutralizing antibodies (bnAbs) CR6261, CR9114 and FI6v3, we selected and optimized molecules that effectively mimic the bnAb functionality. Our lead compound neutralizes influenza A group 1 viruses by inhibiting HA-mediated fusion in vitro, protects mice against lethal and sublethal influenza challenge after oral administration, and effectively neutralizes virus infection in reconstituted 3D-cell culture of fully differentiated human bronchial epithelial cells. Co-crystal structures with H1 and H5 HAs reveal that the lead compound recapitulates the bnAb hotspot interactions.
Audience take away:
• We present proof-of-concept for antibody-guided, small molecule discovery. Starting from a well-characterized antibody with a desired activity profile, we selected and further improved a small molecule ‘antibody mimetic’ that recapitulates the antibody features in vitro and in vivo. 
• The approach addresses the common challenge of effective targeting biologically validated molecular targets by pharmaceutically relevant modalities. The success of this approach demonstrates the advantage of rigorously considering the targeted epitope-specific binding activity in close combination with the associated functional activity and mechanism of action, instead of focusing on potency alone. The strategy allows for the generation of robust structure-activity relationships, thereby yielding a great level of control over the pharmacodynamic and pharmacokinetic properties of the selected ligand classes.