Abstract
Picornaviruses include rhinoviruses and enteroviruses. Rhinoviruses cause millions of cases of upper respiratory infections (“colds”) yearly and contribute to asthma, and enteroviruses are responsible for millions of infections including cases such as meningitis, encephalitis and polio. There are currently no antivirals that can be used for the treatment or prevention of any of the rhino- or enteroviruses.
To replicate, viruses must interact with host cells, and in doing so, often need to change shape; stabilizing the virus particle is therefore thought to be a promising strategy for preventing replication. As an introduction, I will summarize our structural work on picornaviruses especially out RNA-centric model of assembly based on multiple packaging sequences, and then focus on a recent search for potential antiviral candidates, where we have found a compound that stabilized a model picornavirus. We performed cryo-electron microscopy (cryo-EM) of the drug-virus complex to determine how the drug exerted its effect. Cryo-EM involves combining thousands of two-dimensional images to develop a highly detailed three-dimensional structure of the target.
Although picornaviruses have been studied for decades, we discovered a previously unknown pocket, or indentation, on the surface of the virus, in which the compound had lodged, thereby stabilizing it against the kind of shape change that would allow interaction with host cells. We then used the compound as a starting point to generate multiple variants of the antiviral molecule to maximize the activity against a broad range of picornaviruses.
A major challenge in developing antiviral medications is that viruses mutate quickly, changing in ways that make a once-useful drug ineffective. While it is possible that the newly-discovered pocket may also mutate to make picornaviruses resistant to therapies developed against them, we showed that the pocket is crucial enough for viral replication that viruses containing mutant versions are less viable, making the drug relatively “resistance-proof.”
Further work to develop these compounds into effective drugs is ongoing. These results open up a new avenue for the design of broad-spectrum antivirals against rhinoviruses and enteroviruses, both of which are major human pathogens.