The anti-inflammatory drug naproxen is a common over-the-counter painkiller. Now scientists have used the drug to find new leads in the fight against flu. A new study shows that derivatives of the anti-inflammatory drug naproxen block a protein essential for viral replication and act against flu in cell lines and in mice (J. Med. Chem. 2018. DOI: 10.1021/acs.jmedchem.8b00557).
Scientists are eager to add new agents to their antiflu arsenal, especially as the virus shows increasing resistance to antiviral drugs like Tamiflu, and after the especially bad 2017 flu season. The influenza virus contains a protein called the nucleoprotein, which manages expression and replication of the virus’s RNA-based genome. The nucleoprotein’s structure was solved in 2008. In 2013, a team of researchers led by Anny Slama-Schwok of Paris Saclay University, used computer modeling to screen a library of compounds for ones that bound to a groove in the nucleoprotein that normally binds RNA, hoping to find something that could inhibit the nucleoprotein’s function and act as an antiviral.
They targeted this groove because it’s a critical part of an essential protein. “Viruses are tricky. As soon as you develop an antiviral, they mutate and become resistant,” Slama-Schwok says. “The virus is less likely to mutate critical amino acids.” The team’s screen quickly hit upon naproxen, a nonsteroidal anti-inflammatory drug that works by inhibiting COX enzymes in humans. However, the drug has known cardiovascular risks because of its COX-2 activity. So in the new work, the researchers set out to develop naproxen derivatives that bind to the influenza nucleoprotein but ignore COX-2.
Using the crystal structure of the nucleoprotein, the researchers designed four novel naproxen derivatives that fit even more snugly into the RNA binding pocket. The researchers synthesized and tested the compounds and found that none inhibited COX-2. Two of the derivatives showed the most promise as antivirals, with high affinity for binding the nucleoprotein and good stability. The researchers also found that the derivatives effectively blocked the polymerase that replicates the viral genome.
The researchers then tested the derivatives in living cells and animals. Though both of the two most promising derivatives protected human cells from flu, one was particularly effective against a Tamiflu-resistant H1N1 flu virus. The other derivative, the only one they tested in mice, protected the animals entirely from exposure to a lethal flu strain. The researchers suspect the antiviral activity has to do with the derivatives’ ability to block both RNA and the polymerase from binding to the nucleoprotein.
“People are dying from resistant influenza strains, so this is a really important area of study,” says Robert J. Linhardt of Rensselaer Polytechnic Institute. “I think their modeling is an intelligent approach. I like the target they picked because a conserved domain probably won’t mutate.”
Linhardt thinks there is room for improvement: “I think they will probably spend some effort improving their lead compound, increasing binding affinity and checking for toxicity.”