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Drug-like compound hits a vulnerable spot on multiple strains of the flu virus.

LA JOLLA, CA—Scientists from Scripps Research have used a powerful new drug screening method to find a compound that neutralizes multiple strains of influenza virus.

The potential new drug lead compound, described in the Proceedings of the National Academy of Sciences, hits a vulnerable site on flu viruses—the so-called hemagglutinin (HA) stem—whose important role in infecting cells means that it does not vary much from one flu strain to the next.

Certain rare human antibodies can neutralize a broad variety of flu strains by binding to this same HA stem site, but all of the currently approved antiviral flu drugs attack other sites on the virus.

“With this compound, we can start to attack influenza virus in a way that hasn’t been done before with existing flu drugs, and at an early stage of the infection process,” says the study’s senior author Dennis Wolan, PhD, an associate professor in the Department of Molecular Medicine at Scripps Research.

The study was a collaboration between Wolan’s lab and the lab of Ian Wilson, DPhil, Hansen Professor of Structural Biology and Chair of the Department of Integrative Structural and Computational Biology at Scripps Research.

“This is a good step forward in an ongoing effort to find new templates and lead compounds to design drugs that inhibit the influenza virus HA protein,” Wilson says.

There’s a strong need for new drug treatments for influenza. Flu viruses kill more than 50,000 people in the United States every year, and occasionally—as in the 1918 “Spanish flu”—cause pandemics with death tolls in the millions. Existing flu drugs such as Tamiflu (oseltamivir) can be useful in preventing or in treating severe flu cases, but these drugs target sites on flu viruses where the viruses can mutate relatively easily to become drug-resistant.

Existing seasonal flu vaccines also are useful, but have to be updated annually and don’t cover emerging viruses or potential pandemic threats, such as bird flu, and often do not work well in elderly people and others with weakened immune systems.

In recent years, Wilson’s lab and others have studied antibodies isolated from flu patients that can neutralize a broad range of influenza strains. Some of the most potent of these broadly neutralizing antibodies (bnAbs) attack the HA stem. HA proteins stud the surface of a flu virus particle and can attach to certain receptors on cells in the respiratory tract.

Once attached, the HA stem structure normally alters its shape to enable the virus to fuse with the host cell’s outer membrane, thus enabling entry into the cell. Antibodies that bind to the HA stem can block that HA shape-shift from happening and thus prevent viral entry.

The researchers for the new study developed a method for finding potential drug molecules that hit this vulnerable site in the same way that broadly neutralizing antibodies do.

The new method makes use of a peptide called P7, which was originally designed at Janssen Pharmaceutica, to mimic key portions of stem-binding broadly neutralizing antibodies. The method allows researchers to test—in a relatively quick, automated and low-cost way—a large collection of thousands of sample compounds, to find any that compete with P7 to bind to the same tightly defined portion of the HA stem.

Using the new method, the team screened about 72,000 compounds and found one, F0045(S), that powerfully neutralizes multiple H1N1 human influenza strains in vitro—as well as multiple H5N1 “bird flu” strains, which rarely infect humans but carry a high mortality rate when they do. Wilson’s lab used X-ray crystallography to confirm, at atomic resolution, that F0045(S) binds to the influenza HA stem much in the same way as broadly neutralizing antibodies.

F0045(S) on the whole appears to work against the largest family of influenza A HA subtypes, the group 1 HAs, which contain H1N1 human influenza as well as H5N1 and other virus subtypes. Group 2 HAs, which include H3N2 human influenza viruses, and HAs in a separate set of flu viruses called Influenza B viruses, have slightly different structures—and so for these, the researchers expect to have to modify F0045(S) significantly, or screen for new stem-targeting compounds.

“Possibly we would end up with a cocktail of several drug compounds targeting different families of HA proteins to cover most or all flu strains,” Wolan says.

The researchers are now using chemistry techniques to modify F0045(S) to improve its stem-binding affinity and general drug properties, and they expect to continue developing it and related compounds to search for new leads that could be developed into novel flu treatments.

An Influenza A Hemagglutinin Small-Molecule Fusion Inhibitor Identified by a New High-Throughput Fluorescence Polarization Screen” was authored by Yao Yao, Rameshwar Kadam, Chang-Chun Lee, Jordan Woehl, Nicholas Wu, Xueyong Zhu, Seiya Kitamura, Ian Wilson, and Dennis Wolan, all of Scripps Research.

The work was supported by the National Institutes of Health (R56 AI127371, K99 AI39445) and the Bill and Melinda Gates Foundation (OPP1170236).