New potent EV-A71 antivirals targeting capsid.

ABSTRACT

The 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 for numerous diseases and some infections can progress to life-threatening complications, particularly in children or immunocompromised patients. To date, there is no treatment against enteroviruses on the market, except for polioviruses (vaccine) and EV-A71 (vaccine in China). Following a decrease in enterovirus infections during and shortly after the (SARS-Cov2) lockdown, enterovirus outbreaks were once again detected, notably in young children. This reemergence highlights on the need to develop broad-spectrum treatment against enteroviruses. Over the last year, our research team has identified a new class of small-molecule inhibitors showing anti-EV activity. Targeting the well-known hydrophobic pocket in the viral capsid, these compounds show micromolar activity against EV-A71 and a 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, CC50, MRC-5 > 20 µM, EC50, RD = 0.53 µM, CC50, RD > 40 µM, SI > 63). The binding mode of these compounds in complex with enterovirus capsids was analyzed and showed a series of conserved interactions. Consequently, 6c and its derivatives are promising candidates for the treatment of enterovirus infections.