Alpha-ketoamides as broad-spectrum inhibitors of coronavirus and enterovirus replication

Linlin Zhang; Daizong Lin; Yuri Kusov; Yong Nian; Qingjun Ma; Jiang Wang; Albrecht von Brunn; Pieter Leyssen; Kristina Lanko; Johan Neyts; Adriaan de Wilde; Eric J. Snijder; Hong Liu; Rolf Hilgenfeld

In spite of the considerable threat posed by SARS-CoV and related viruses, as well as by MERS-CoV, it is obvious that the number of cases so far does not warrant the commercial development of an antiviral drug targeting MERS-and SARS-CoV even if a projected steady growth of the number of MERS cases is taken into account. A possible solution to the problem could be the development of broadspectrum antiviral drugs that are directed against the major viral protease, a target that is shared by all coronavirus genera as well as, in a related form, by members of the large genus Enterovirus in the picornavirus family. Among the members of the genus Alphacoronavirus are the human coronaviruses (HCoV) NL63 (ref. 9) and 229E 10 that usually cause only mild respiratory symptoms in otherwise healthy individuals, but are much more widespread than SARS-CoV or MERS-CoV. Therapeutic intervention against alphacoronaviruses is indicated in cases of accompanying disease such as cystic fibrosis 11 or leukemia, 12 or certain other underlying medical conditions. 13 The enteroviruses include pathogens such as EV-D68, the causative agent of the 2014 outbreak of the "summer flu" in the US, 14 EV-A71 and Coxsackievirus A16 (CVA16), the etiological agents of Hand, Foot, and Mouth Disease (HFMD), 15 Coxsackievirus B3 (CVB3), which can cause myocardic inflammation, 16 and human rhinoviruses (HRV), notoriously known to lead to the common cold but also capable of causing exacerbations of asthma and COPD. 17 Infection with some of these viruses can lead to serious outcome; thus, EV-D68 can cause polio-like disease, 18 and EV-A71 infection can proceed to aseptic meningitis, encephalitis, pulmonary edema, viral myocarditis, and acute flaccid paralysis. 15, [19] [20] Enteroviruses cause clinical disease much more frequently than coronaviruses, so that an antiviral drug targeting both virus families should be commercially viable.