Computationally Designed Cyclic Peptides Derived from an Antibody Loop Increase Breadth of Binding for Influenza Variants

The influenza hemagglutinin (HA) glycoprotein is the target of many broadly neutralizing antibodies. However, influenza viruses can rapidly escape antibody recognition by mutation of hypervariable regions of HA that overlap with the binding epitope. We hypothesized that by designing peptides to mimic antibody loops, we could enhance breadth of binding to HA antigenic variants by reducing contact with hypervariable residues on HA that mediate escape. We designed cyclic peptides that mimic the heavy-chain complementarity-determining region 3 (CDRH3) of anti-influenza broadly neutralizing antibody C05 and show that these peptides bound to HA molecules with <100 nM affinity, comparable with that of the full-length parental C05 IgG. In addition, these peptides exhibited increased breadth of recognition to influenza H4 and H7 subtypes by eliminating clashes between the hypervariable antigenic regions and the antibody CDRH1 loop. This approach can be used to generate antibody-derived peptides against a wide variety of targets.