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

A number of capped dipeptidyl a-ketoamides have been described as inhibitors of the norovirus 3C-like protease. 41 These were optimized with respect to their P1' substituent, whereas P2 was isobutyl in most cases and occasionally benzyl. The former displayed IC50 values one order of magnitude lower than the latter, indicating that the S2 pocket of the norovirus 3CL protease is fairly small. Although we did not include the norovirus 3CL pro in our study, expanding the target range of our inhibitors to norovirus is probably a realistic undertaking. While our study was underway, Zeng et al. 42 published a series of a-ketoamides as inhibitors of the EV-A71 3C pro . These authors mainly studied the structure-activity relationships of the P1' residue and found small alkyl substituents to be superior to larger ones. Interestingly, they also reported that a six-membered d-lactam in the P1 position led to 2 -3 times higher activities, compared to the fivemembered g-lactam. At the same time, Kim et al. 43 described a series of five a-ketoamides with P1' = cyclopropyl that showed submicromolar activity against EV-D68 and two HRV strains.