Phage capsid nanoparticles with defined ligand arrangement block influenza virus entry
D. Lauster, S. Klenk, K. Ludwig, S. Nojoumi, S. Behren, L. Adam, M. Stadtmüller, S. Saenger, [...], U. Hoffmann, M. Bardua, A. Hamann, T. Wolff, [...] K. Osterrieder, N. Budisa, R. R. Netz, C. Böttcher, S. Liese, A. Herrmann, C. P. R. Hackenberger – 2020
Multivalent interactions at biological interfaces occur fre-quently in nature and mediate recognition and interactions in essential physiological processes such as cell-to-cell adhesion. Multivalency is also a key principle that allows tight binding between pathogens and host cells during the initial stages of infection. One promising approach to prevent infection is the design of synthetic or semisynthetic multivalent binders that interfere with pathogen adhesion1–4. Here, we present a mul-tivalent binder that is based on a spatially defined arrange-ment of ligands for the viral spike protein haemagglutinin of the influenza A virus. Complementary experimental and theo-retical approaches demonstrate that bacteriophage capsids, which carry host cell haemagglutinin ligands in an arrange-ment matching the geometry of binding sites of the spike pro-tein, can bind to viruses in a defined multivalent mode. These capsids cover the entire virus envelope, thus preventing its binding to the host cell as visualized by cryo-electron tomog-raphy. As a consequence, virus infection can be inhibited in vitro, ex vivo and in vivo. Such highly functionalized capsids present an alternative to strategies that target virus entry by spike-inhibiting antibodies5 and peptides6 or that address late steps of the viral replication cycle7.