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.