Author: 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
Title: Alpha-ketoamides as broad-spectrum inhibitors of coronavirus and enterovirus replication Document date: 2020_2_10
ID: 7n8p9okf_4
Snippet: As the proteases targeted in our study all specifically cleave the peptide bond following a P1-glutamine residue (HCoV-NL63 M pro uniquely also accepts P1 = His at the Nsp13/Nsp14 cleavage site 31 ), we decided to use a 5-membered ring (g-lactam) derivative of glutamine (henceforth called GlnLactam) as the P1 residue in all our aketoamides (see Scheme 1). This moiety has been found to be a good mimic of glutamine and enhance the power of the inhi.....
Document: As the proteases targeted in our study all specifically cleave the peptide bond following a P1-glutamine residue (HCoV-NL63 M pro uniquely also accepts P1 = His at the Nsp13/Nsp14 cleavage site 31 ), we decided to use a 5-membered ring (g-lactam) derivative of glutamine (henceforth called GlnLactam) as the P1 residue in all our aketoamides (see Scheme 1). This moiety has been found to be a good mimic of glutamine and enhance the power of the inhibitors by up to 10-fold, most probably because compared to the flexible glutamine side-chain, the more rigid lactam leads to a reduction of the loss of entropy upon binding to the target protease. 29, 32 Our synthetic efforts therefore aimed at optimizing the substituents at the P1', P2, and P3 positions of the a-ketoamides.
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