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: EC_{50, MRC-5} = 0.57 μM, CC_{50, MRC-5} >20 μM, SI > 35; EC_{50, RD} = 4.38 μM, CC_{50, RD} > 40 μM, SI > 9; 6c: EC_{50, MRC-5} = 0.29 μM, CC_{50, MRC-5} >20 μM, SI > 69; EC_{50, RD} = 1.66 μM, CC_{50, RD} > 40 μM, SI > 24; Reference: Vapendavir EC_{50, MRC-5} = 0.36 μM, CC_{50, MRC-5} > 20 μM, EC_{50, RD} = 0.53 μM, CC_{50, 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.

Keywords: Capsid binder; EV-A71; Heterocyclic compounds; Structure-activity relationships; Structure-based drug design.