Development of Peptide-Oligonucleotide Hybrid Biopolymers as Flu Type-Independent Affinity Reagents

Influenza A virus consistently causes seasonal endemics and continuously poses a pandemic threat, recognized as a worldwide health concern and global economic burden. The frequent mutations in the viruses not only allow them to escape previously induced immunity, but also reduce the effectiveness of existing vaccines and drugs against newly evolved viruses. In this study, we demonstrate the development of novel peptide-oligonucleotide hybrid biopolymers, capable of recognizing a wide breadth of influenza viral strains. We found that regardless of genetic lineage and mutation, the influenza viruses share the common surface domains that bind to host cell receptors for infection. Since the conserved region is sterically hindered by the cave-like indented geometry, it can be accessed by relatively small molecules only. Presumably, a minimal peptide can be constructed by a computational redesign to broadly targets influenza viruses by incorporating the conserved viral epitopes into its compact size. However, it faces challenges due to its poor binding affinity and low solubility under biological conditions. To address this, through our systematic in vitro screening technology, we successfully generated a hybrid biopolymer by the conjugating minimal peptide with oligonucleotide, enhancing molecular binding affinity over 10 times compared to the original peptide. The oligonucleotide serves as a supporting scaffold structure for synergistic binding and extends the applicability of the developed hybrid biopolymers to therapeutics and diagnostics due to the its programmability. The hybrid biopolymer shows great potential for exhibiting binding tolerance to other classes of influenza, thereby overcoming current and upcoming immune escapes.