Multivalent interactions at biological interfaces occur frequently 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 adhesion1,2,3,4. Here, we present a multivalent binder that is based on a spatially defined arrangement of ligands for the viral spike protein haemagglutinin of the influenza A virus. Complementary experimental and theoretical approaches demonstrate that bacteriophage capsids, which carry host cell haemagglutinin ligands in an arrangement matching the geometry of binding sites of the spike protein, 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 tomography. 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.
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The data supporting the findings of this study are available within the paper and its Supplementary Information. All relevant data are available from the authors upon reasonable request. Model coordinates of the HA–Sia binding pockets and the Qβ capsid surface are taken from the Protein Data Bank under accession numbers 1HGG and 1QBE, respectively.
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We thank Andrew K. Udit for providing the Qβ(K16M) plasmid and L. Artner for synthetic contributions. This work was supported by the German Research Foundation (DFG, SFB765, SPP1623 and SFB-TR84) and the Germany Ministry of Education and Research (BMBF, RAPID) as well as Charité 3R and the Einstein Foundation Berlin.
The authors declare no competing interests.
Peer review information Nature Nanotechnology thanks Andrew Ward and the other, anonymous, reviewers for their contribution to the peer review of this work.
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Lauster, D., Klenk, S., Ludwig, K. et al. Phage capsid nanoparticles with defined ligand arrangement block influenza virus entry. Nat. Nanotechnol. 15, 373–379 (2020). https://doi.org/10.1038/s41565-020-0660-2
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