Posted January 20, 2015

Discovery may help fight flu

Greg Fornia, SMC '92
Researchers Eleonora Gianti and Giacomo Fiorin of Temple’s Institute for Computational Molecular Science display molecular simulations of a potential flu drug.

A team of Temple scientists has discovered a possible way of inhibiting influenza.

The research of Eleonora Gianti and Giacomo Fiorin of Temple’s Institute for Computational Molecular Science (ICMS) and Michael L. Klein, ICMS director and dean of Temple’s College of Science and Technology, shows promise for developing more effective antiviral drugs that can be used in the treatment of emerging mutant strains of the virus.

Their findings, “Flipping in the Pore: Discovery of Dual Inhibitors That Bind in Different Orientations to the Wild-Type Versus the Amantadine Resistant S31N Mutant of the Influenza A Virus M2 Proton Channel,” were published in the December issue of the Journal of the American Chemical Society.

Each year, the influenza virus—the pathogen responsible for the flu—affects millions of people around the world. During an annual flu season, an estimated 35,000 people die due to influenza-related illnesses, which places influenza among the top 10 leading causes of death in the U.S., according to research published in the Journal of the American Medical Association.

The Centers for Disease Control and Prevention estimates that during the current flu season, the flu vaccine—which can prevent people from getting the flu—is only 23 percent effective, which means antiviral treatment, for people who already have the flu, is especially important.

But with the two main antiviral drugs used to treat the flu, Tamiflu and Relenza, becoming increasingly ineffective against the emerging mutant strains of the virus, the search for new drugs that are effective against all versions of the virus is taking on new urgency.         

Gianti and Fiorin discovered a peculiar quirk in how an older, now obsolete drug called amantadine binds to the original form of the virus—the wild type—and the emerging mutant strains.

“This research produced a new derivative of the amantadine molecule that can serve as a dual inhibitor of the flu, by binding to a protein of the mutant virus in one particular orientation—facing away from it—while the same molecule binds to the protein of the wild-type virus facing toward it,” explained Gianti, a postdoctoral fellow in chemistry.

“This peculiar mechanism of binding was revealed through both experimental data in the lab [at the University of California, San Francisco] and molecular simulations with supercomputers [at Temple’s ICMS],” she said.        

Knowing how this new molecule binds to both types of the virus gives researchers a significant head start in designing more powerful and effective drugs.

The research team’s discovery is the first evidence of a molecule that works against both versions of the viral protein, said Fiorin, assistant professor of biology.

“Now it’s down to fine-tuning the chemical structure of this new inhibitor to preserve its ability to bind to and inhibit wild type and mutant simultaneously and make it more effective,” he said. “We’ve found a good template; now we have to optimize it.”       

According to Fiorin, optimizing amantadine derivatives and developing an entirely new class of antivirals is vital; Tamiflu still works, but emergent strains may take over the entire flu population and render Tamiflu ineffective within a decade.

“We need a way to stop the virus as soon as possible, especially in patients who have an impaired immune system,” he said. “They are most at risk. Our research gets us much closer to that goal.”