The indentation could be a target for new drugs effective against the pathogens
IN THE POCKET A chemical compound (illustrated at center) binds to a never-before-seen pocket on the protein shell (blue, white and magenta) of an enterovirus, preventing replication.
A newly discovered indentation on the surface of viruses that cause many illnesses, including the common cold, could be their Achilles’ heel — and a possible target for effective drugs.
When scientists tested antiviral compounds on cells grown in the lab, the team found one that blocked the replication of an enterovirus. Cryo-electron microscopy revealed that the compound binds to and appears to jam a previously unknown pocket on the virus’s protein shell, researchers report online June 11 in PLOS Biology.
Additional testing suggests that the pocket is widespread among picornaviruses, the viral family that includes enteroviruses — which cause hand, foot and mouth disease as well as more dangerous infections — and rhinoviruses, responsible for the common cold. There are no antiviral medications available to treat these pathogens.
The pocket “is an excellent target for antivirals” that may be effective against many of these types of viruses, says Susan Hafenstein, a structural virologist with the College of Medicine at Penn State who was not involved in the study.
These viruses mutate very frequently, which makes it “easier for them to escape a drug,” she says. To identify drug targets in the viruses, “it is essential to identify key working components” that these pathogens need to survive.
During an infection, viruses inject their genetic material into cells and take over the cellular machinery to make more viral particles. In picornaviruses, a protein shell surrounds the virus’s inner core of genetic material. Previous research suggests the shell changes shape when these viruses are ready to expel their genetic payload during an infection.
But a chemical compound, identified by structural virologist Sarah Butcher of the University of Helsinki, virologist Johan Neyts of the University of Leuven in Belgium and colleagues, binds to the newly discovered pocket in the protein shell and appears to lock the pocket in place. “This locking prevents the virus from infecting cells,” says Butcher, because the shell can’t change its shape and release its genetic material.
The researchers then tested other similar compounds, and found they were able to block many other picornaviruses, an indication that the pocket is a shared feature throughout the family with a crucial role in the viral life cycle, Butcher says.
The team is now altering those compounds to enhance their properties for use as drugs against this viral Achilles’ heel, Neyts says.