Novel engineered molecule inhibits influenza virus replication
Seah Yee Mey
Scientists have recently identified and developed a novel class of molecules that appears to inhibit influenza virus replication, a new study reports. [ACS Chemical Biology 2013; doi: 10.1021/cb400400j]
Researchers at Rutgers University, New Jersey, US, engineered part of the influenza virus replication enzyme and used it to screen a library of 800 small molecule fragments for potential sites of enzyme inhibition.
Fragment screening led them to the discovery of a previously unknown metal ion binding location in the active site of the enzyme that could be exploited to inhibit viral replication. Based on the screen, the researchers then designed a new class of compounds to selectively block the influenza virus’ enzymatic activity. When tested on cell cultures, the compounds demonstrated antiviral activity.
“We’re at a key proof of principle stage right now,” said Eddy Arnold, professor of chemistry and chemical biology at Rutgers, whose laboratory carried out the research in collaboration with Edmond LaVoie, professor and chair of medicinal chemistry also at Rutgers, and virologist Luis Martinez-Sobrido of the University of Rochester, New York. “It’s not trivial to go from this point to actually delivering a drug, but we’re optimistic – this class of inhibitors has all the right characteristics,” he said.
Just as bacteria develop antibiotic resistance, Arnold noted that some strains of influenza have also started to develop resistance to oseltamivir phosphate, which is currently the only orally available anti-influenza drug. Therefore, Arnold and his collaborators are searching for other drugs, especially ones that target other parts of the virus. They selected this particular viral enzyme because inhibiting its activity interferes with the virus’ ability to ‘steal’ material from human cells and disguise itself.
The approach used by Arnold and his collaborators has also helped in the development of anti-HIV drugs. Merck targeted metal ion-containing active sites in an HIV enzyme to develop a successful anti-HIV drug. “It’s truly remarkable what they did, and we’re trying to pursue similar logic with influenza,” Arnold said.
Antiviral drug discovery is an essential alternative to vaccines, especially during pandemics when timely vaccine production is difficult. While this approach is not new, the technology to produce the high-resolution images of the H1N1 influenza enzyme structure used by the Rutgers researchers to screen for inhibitors is only recently available.