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.

流感血凝素 (HA) 糖蛋白是许多广泛中和抗体的目标。然而，流感病毒可以通过与结合表位重叠的 HA 高变区的突变而迅速逃脱抗体识别。我们假设通过设计肽来模拟抗体环，我们可以通过减少与 HA 上介导逃逸的高变残基的接触来增强与 HA 抗原变体的结合广度。我们设计了模拟抗流感广泛中和抗体 C05 的重链互补决定区 3 (CDRH3) 的环肽，并表明这些肽以 <100 nM 的亲和力与 HA 分子结合，与全长亲本的亲和力相当C05 IgG。此外，通过消除高变抗原区域和抗体 CDRH1 环之间的冲突，这些肽表现出对流感 H4 和 H7 亚型的识别范围增加。这种方法可用于生成针对多种靶标的抗体衍生肽。