Science 358, 496–502 (2017)

The major glycoprotein hemagglutinin (HA) binds to sialylated receptors of the host cell, enabling endocytotic uptake of the influenza virus. Acidification in late endosomes triggers a conformational change in the stem region of the HA homotrimer, leading to virus and host cell-membrane fusion. Currently, none of the influenza drugs approved worldwide target HA. Kadam et al. designed inhibitory peptides based on complementarity determining region (CDR) loops of broadly neutralizing antibodies (bnAb) that bind the conserved HA stem and block the HA conformational changes required for membrane fusion. Starting with linear peptides, the authors varied their length and sequence, constrained the peptide conformation by cyclization and characterized HA subtype binding specificities and affinities. They then introduced nonproteinogenic amino acids to further increase HA binding affinity. The optimized cyclic peptides have nanomolar affinities and were effective in virus neutralization assays. The cyclic-peptide-bound HA crystal structures revealed that the peptides bind in a manner very similar to the bnAb CDR loops. The structures that were determined at low pH, as well as biochemical experiments, showed that the peptides inhibit viral fusion by stabilizing the HA prefusion state. The cyclic peptides are stable in plasma and not cytotoxic, which corroborates their potential for influenza drug development.