Given the current global viral pandemic, it wouldn’t be difficult for most to think of viruses in only a negative context. However, over the past several years, a slew of researchers and data has come to light on the benefits of using phage viruses as therapeutic options. Now, a team of investigators led by scientists at the Leibniz-Forschungsinstitut for Molecular Pharmacology (FMP) and Humboldt University (HU) has found a new use for phage in the fight against seasonal influenza and avian flu. The researchers developed a chemically modified phage capsid that “stifles” influenza viruses. Perfectly fitting binding sites cause influenza viruses to be enveloped by the phage capsids in such a way that it is practically impossible for them to infect lung cells any longer. This phenomenon has been proven in preclinical trials using human lung tissue and is being used for the immediate investigation of coronavirus infections.

Findings from the new study were published recently in Nature Nanotechnology through an article entitled “Phage capsid nanoparticles with defined ligand arrangement block influenza virus entry.”

Current antiviral drugs are only partially effective because they attack viruses like influenza and coronavirus after lung cells have been infected. It would be desirable—and much more effective—to prevent infection in the first place. This is exactly what the new approach from the current study promises. The phage capsid, developed by a multidisciplinary team of researchers, envelops flu viruses so perfectly that they can no longer infect cells.

“Preclinical trials show that we are able to render harmless both seasonal influenza viruses and avian flu viruses with our chemically modified phage shell,” explained senior study investigator Christian Hackenberger PhD, head of the department chemical biology at FMP and a professor for chemical biology at HU. “It is a major success that offers entirely new perspectives for the development of innovative antiviral drugs.”

The new inhibitor makes use of a feature that all influenza viruses have: There are trivalent receptors on the surface of the virus, referred to as hemagglutinin protein, that attaches to sugar molecules (sialic acids) on the cell surface of lung tissue. In the case of infection, viruses hook into their victim—in this case, lung cells—like a hook-and-loop fastener. The core principle is that these interactions occur due to multiple bonds, rather than single bonds.

It was the surface structure of flu viruses that inspired the researchers to ask the following initial question more than six years ago: Would it not be possible to develop an inhibitor that binds to trivalent receptors with a perfect fit, simulating the surface of lung tissue cells? The answer to the question lies with Q-beta phage, which has the ideal surface properties and is excellently suited to equip it with ligands—sugar molecules—as “bait.” An empty phage shell does the job perfectly.

“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,” the authors wrote. “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.”

Lead study investigator Daniel Lauster, PhD, a former graduate student in the Group of Molecular Biophysics (HU) and now a postdoc at Freie Universität Berlin added that “Our multivalent scaffold molecule is not infectious, and comprises 180 identical proteins that are spaced out exactly as the trivalent receptors of the hemagglutinin on the surface of the virus. It, therefore, has the ideal starting conditions to deceive the influenza virus—or, to be more precise, to attach to it with a perfect spatial fit. In other words, we use a phage virus to disable the influenza virus!”

To enable the Q-beta scaffold to fulfill the desired function, it must first be chemically modified. Produced from E. coli bacteria, the researchers used synthetic chemistry to attach sugar molecules to the defined positions of the virus shell.

Several studies using animal models and cell cultures have proven that the suitably modified spherical structure possesses considerable bond strength and inhibiting potential. The study also enabled the research team to examine the antiviral potential of phage capsids against many current influenza virus strains, and even against avian flu viruses. Its therapeutic potential has even been proven on human lung tissue: when tissue infected with flu viruses was treated with the phage capsid, the influenza viruses were practically no longer able to reproduce.

Additionally, high-resolution cryo-electron microscopy and cryo-electron microscopy show directly and, above all, spatially, that the inhibitor completely encapsulates the virus. Moreover, mathematical-physical models were used to simulate the interaction between influenza viruses and the phage capsid on the computer.

“Our computer-assisted calculations show that the rationally designed inhibitor does indeed attach to the hemagglutinin, and completely envelops the influenza virus,” confirmed study co-author Susanne Liese, PhD, professor at Freie Universität Berlin. “It was therefore also possible to describe and explain the high bond strength mathematically.”

These findings must now be followed up by more preclinical studies. It is not yet known, for example, whether the phage capsid provokes an immune response in mammals. Ideally, this response could even enhance the effect of the inhibitor. However, it could also be the case that an immune response reduces the efficacy of phage capsids in the case of repeated-dose exposure, or that flu viruses develop resistances. And, of course, it has yet to be proven that the inhibitor is also effective in human

“Our rationally developed, three-dimensional, multivalent inhibitor points to a new direction in the development of structurally adaptable influenza virus binders. This is the first achievement of its kind in multivalency research,” Hackenberger concluded.

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