ALMA — Three years after receiving a $150,000 National Science Foundation grant, faculty-directed undergraduate students at Alma College have developed a molecule that inhibits certain strains of the human influenza virus.
The grant through the NSF’s Research in Undergraduate Institutions program, awarded in August 2009, supported the synthesis of a new generation of neuraminidase inhibitors that principal investigator Jeff Turk says could guide the future development of antiviral drugs.
“We have made significant progress,” said Turk, assistant professor of chemistry. “The influenza virus spreads in the body by an enzyme-mediated pathway. The neuraminidase enzyme found on the surface of the influenza virus is responsible, in part, for the spread of the virus. If we can create a molecule that inhibits the neuraminidase protein, we can slow or even halt the spread of the virus.”
Turk initially designed a series of small molecules that were shown by computer modeling to have the potential to bind inside the neuraminidase protein and inhibit the influenza infection. Over the course of the NSF grant, Turk and his students synthesized, evaluated and modified the molecules.
“This past summer, we synthesized a lead compound that has shown the ability to inhibit the neuraminidase enzyme by 95 percent — meaning only 5 percent of the enzyme remains active,” says Turk. “With this accomplishment, we are now at a jumping point in our research. Our next steps are to build on this lead compound. We will be seeking additional grant funding to extend our research.”
Not all neuraminidase proteins are structured the same, says Turk. Research teams across the country synthesize and modify different molecule constructions that target specific strains of influenza. Alma’s lab has focused on the H1N1 virus, commonly known as swine flu.
“Other labs are producing successful molecules, but all are different and unique in their construction,” he said. “When researchers publish their findings, we all learn about the kinds of molecules that may be most effective. Tamiflu, the prescribed medicine most often used now to treat most forms of influenza, inhibits the neuraminidase enzyme close to 100 percent like ours, but the concentration required to do it is much less than ours. There is still a lot of work to do, but our molecule has shown the potential of being developed into a drug that inhibits the virus at the same magnitude as Tamiflu.”
Alma’s research has received an external endorsement from James Stevens, a scientist and team lead in the Virology Surveillance and Diagnosis Branch of the Influenza Division at the Centers for Disease Control and Prevention.
“The ability to acquire relevant viral strains for laboratory research hinges on funding; they are expensive,” Turk said. “Dr. Stevens has reviewed our research and has agreed to send us modern viral enzymes at no cost. Also, we do not have the expertise or equipment to x-ray crystal structures of our molecules cocrystallized with the enzyme — a process that produces a three-dimensional picture of what the molecule looks like. Dr. Stevens has agreed to do the cocrystalization of our molecule. That’s a major step for us.”
Turk and project collaborator Joe Beckmann, professor of biochemistry at Alma College, actively engage undergraduate students in their research. Over the course of the NSF grant, 12 students have participated in the project, and 11 students have presented research findings at local and national American Chemical Society meetings.
Beckmann assisted the students in evaluating the binding effectiveness and mechanisms of the synthetic molecules.
“Medicinal chemistry is a field typically reserved for graduate programs, but involving undergraduate students in the drug-discovery process has proven to have an invaluable impact on their learning,” Turk said. “They confront firsthand important questions: Why are we making this molecule? Why are we shaping it this way? What are the interactions with the targeted enzyme? They follow the project from inception, through synthesis, then testing.”
Turk and Beckmann described their efforts in involving undergraduate students in medicinal chemistry research in a recently published article in the Journal of Chemical Education titled “Resources for an Investigative and Sustainable Undergraduate Medicinal Chemistry Research Program.”
“The pedagogical reasons for involving undergraduates in this kind of research is just as important as the scientific output,” Turk said. “We have made significant progress on our research because of the efforts of our undergraduates students. This is a culmination of only three summers of work, and the progress they have made is very commendable.”