Novel NSAID-Se derivative YSN-1-167 against Enterovirus 71 infection by inhibiting 3D^pol activity

Hand, foot, and mouth disease (HFMD) is primarily caused by Enterovirus 71 (EV71) and Coxsackievirus A16 (CA16), while excessive inflammatory responses induced by viral infection are the main cause of severe conditions. Hence, it is important to develop agents with both antiviral and anti-inflammatory activities for clinical treatment. In this study, we synthesized 20 compounds based on the hybridization of nonsteroidal anti-inflammatory drugs (NSAIDs) and organoselenium and found that YSN-1-167 exhibited significant anti-EV71 function using an EV71-GFP infection system. Mechanistic studies showed that this compound suppressed virus replication but not the binding and entry steps, and further target screening found that YSN-1-167 might suppress 3D polymerase function but not viral 2A and 3C proteases. The conservation of 3D polymerase between EV71 and CA16 prompted us to discover that YSN-1-167 can also significantly inhibit CA16 infection. As expected, this compound can reduce the levels of pro-inflammatory mediators, including IL-1β and COX-2, induced by EV71 infection. Furthermore, YSN-1-167 exhibited favorable safety and effective anti-EV71 and anti-inflammatory properties in neonatal mice. In conclusion, these results suggested that YSN-1-167 can be developed into a potential therapeutic strategy for HFMD induced by EV71 and CA16 via inhibiting virus replication and inflammatory response.