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

Seventeen years have passed since the outbreak of severe acute respiratory syndrome (SARS) in 2003, but there is yet no approved treatment for infections with the SARS coronavirus (SARS-CoV). 1 One of the reasons is that despite the devastating consequences of SARS for the affected patients, the development of an antiviral drug against this virus would not be commercially viable in view of the fact that the virus has been rapidly contained and did not reappear since 2004. As a result, we were empty-handed when the Middle-East respiratory syndrome coronavirus (MERS-CoV), a close relative of SARS-CoV, emerged in 2012. 2 MERS is characterized by severe respiratory disease, quite similar to SARS, but in addition frequently causes renal failure 3 . Although the number of registered MERS cases is low (2494 as of November 30, 2019; www.who.int), the threat MERS-CoV poses to global public health may be even more serious than that presented by SARS-CoV. This is related to the high casefatality rate (about 35%, compared to 10% for SARS), and to the fact that MERS cases are still accumulating seven years after the discovery of the virus, whereas the SARS outbreak was essentially contained within 6 months. The potential for human-to-human transmission of MERS-CoV has been impressively demonstrated by the 2015 outbreak in South Korea, where 186 cases could be traced back to a single infected traveller returning from the Middle East. 4 SARS-like coronaviruses are still circulating in bats in China, [5] [6] [7] [8] from where they may spill over into the human population; this is probably what caused the current outbreak of atypical pneumonia in Wuhan, which is linked to a seafood and animal market. The RNA genome (Gen-Bank accession code: MN908947.2; http://virological.org/t/initialgenome-release-of-novel-coronavirus/319, last accessed on January 11, 2020) of the new betacoronavirus features around 82% identity to that of SARS-CoV.