New Potent EV-A71 Antivirals Targeting Capsid

Enterovirus is a genus of single-stranded, highly diverse positive-sense RNA viruses, including Human Enterovirus A-D and Human Rhinovirus A-C species. They are responsible of numerous diseases and some infections can progress to life-threatening complications, particularly in children or immunocompromised patients. To date, no treatment is commercialized against enteroviruses, except for polioviruses (vaccine) and EV-A71 (vaccine in China). After a decrease in enterovirus infections during and shortly after the (SARS-Cov2) lockdown, enteroviruses outbreaks were once again detected, notably with a greater sensitivity in young children. This reemergence puts the spotlight on the need to develop broad-spectrum treatment against enteroviruses. Our research team has identified a new class of small-molecules inhibitors showing anti-EV activity. They target the well-known hydrophobic pocket in the viral capsid. These compounds have a micromolar activity against EV-A71 and present high selectivity index (SI) (5h: EC50, MRC-5 = 0.57 µM, CC50, MRC-5 >20 µM, SI >35; EC50, RD = 4.38 µM, CC50, RD > 40 µM, SI > 9; 6c: EC50, MRC-5 = 0.29 µM, CC50, MRC-5 >20 µM, SI >69; EC50, RD = 1.66 µM, CC50, RD > 40 µM, SI > 24; Reference: Vapendavir EC50, MRC-5 = 0.36 µM, EC50, RD = 0.53 µM, CC50, RD > 40 µM, SI > 63). The analysis of the binding mode of these compounds in complex with the enterovirus capsids has been studied and showed a series of conserved interactions. Consequently, 6c and its derivatives are promising candidates for the treatment of enterovirus infections.