Pharmacology of novel approaches designed to target picornaviral infections

Many Picornaviridae family members infect humans. Enterovirus (EV), the largest genus, causes diseases ranging from the common cold to fatal heart disease and paralysis. Human parechoviruses (HPeV) are at least as prevalent as EVs. Currently, no antipicornavirus drugs are used clinically and the large number of viruses precludes vaccination. New drugs are therefore required. Picornavirus infection exploits viral and host proteins, lipids and cellular systems, all potentially targetable by inhibitors. In addition to compounds with a known target, natural products are potential sources of new drugs. Plant material such as berries are cheap, and some extracts have proven antiviral activity. The aim of this project was to repurpose known drugs, approved and used for several years for various medical indications, as well as identify new compounds from natural sources. Coxsackievirus A9 (CAV9) was used as a typical enterovirus and a plaque reduction assay was used to assess antivirus activity. Both approaches gave promising agents. Fluoxetine and dibucaine caused a complete CAV9 inhibition at low concentrations. All drug resistant mutants (DRM) against these compounds had a protein 2C I227V mutation, suggesting this protein is targeted, in accord with previous work on coxsackievirus B3. The identification of DRMs with a single mutation suggests that drug resistance could be problematical if dibucaine and fluoxetine are used clinically. A previously observed interaction between lipid droplets (LDs) and CAV9 and HPeV1 led to studies of LD targeting agents. DGAT inhibitors A922500 and betulinic acid were the most active compounds, in addition to promising results from aspirin and metformin. Redcurrant extract showed antiviral activity, in addition to antioxidant and photodynamic activity. Some microalgae extracts also showed antiviral effects. Although much works remains to be done to fully develop these novel approaches, they have great potential to combat the serious effect of picornavirus infections.