German researchers have "taught" bacteriophages to neutralize the influenza virus and prevent it from entering target cells. Now, scientists have begun similar experiments to neutralize the new SARS-CoV-2 coronavirus.

Modern antiviral drugs neutralize the virus once it has entered the host cell: they disrupt its replication, self-assembly, and so on. Preventing the virus from entering the cell is far more effective. This can be done, for example, with specific antibodies. Scientists from the Leibniz Institute of Molecular Pharmacology and Humboldt University used the Q-beta bacteriophage capsid to neutralize the influenza virus outside the cell, creating a three-dimensional multivalent influenza virus inhibitor based on it. Their work is described in a recent article in Nature Nanotechnology*. The authors chemically modified the empty (nucleic acid-free) protein capsid of the Q-beta bacteriophage so that it specifically binds to molecules on the surface of the influenza virus. As a result, the phage capsids (called nanoparticles by the authors) densely coated the surface of the influenza virus, preventing it from penetrating the target cell for replication.

When the influenza virus interacts with a target cell, its hemagglutinin forms multiple bonds with sialic acids on the surface of lung cells. This multiple bonding creates a zipper-like interaction that is extremely strong. Scientists set out to create something that would mimic the hemagglutinin binding sites and "distract" the influenza virus. The Q-beta phage capsid, whose surface was equipped with numerous sialic acid residues, was ideal for this purpose. Their spatial geometry ensured a strong bond with the influenza virus hemagglutinin molecules.

The bacteriophage capsid that was used does not have infectious properties (since it does not contain nucleic acid) and consists of 180 identical protein subunits, which ensure spatial correspondence between the surfaces of the phage capsid and the influenza virus.

In vitro and animal experiments, modified bacteriophage capsids effectively prevented particles of various seasonal influenza strains, as well as avian influenza, from entering lung cells. The interaction between phage nanoparticles and the influenza virus was stable and long-lasting. Specifically, phage nanoparticles were effective in experiments on human lung tissue cultures: when tissue infected with the influenza virus was treated with phage nanoparticles, the influenza virus virtually ceased replication. Their interaction was also studied using cryo-electron microscopy, which showed that the phage nanoparticles virtually "cover" the influenza virus from all sides.

Scientists are currently investigating whether the introduction of phage nanoparticles into mammals triggers an immune response. This response could either enhance the influenza virus's neutralization or weaken it by neutralizing the phage inhibitor. Research has also begun into the possibility of creating similar three-dimensional multivalent inhibitors for the novel coronavirus that causes COVID-19.

*Lauster D, Klenk S, Ludwig K et al. Phage capsid nanoparticles with defined ligand arrangement block influenza virus entry. Nat. Nanotechnol, Published March 30, 2020. https://doi.org/10.1038/s41565-020-0660-2