α-Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment

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

*Corresponding author for this work
96 Citations (Scopus)

Abstract

The main protease of coronaviruses and the 3C protease of enteroviruses share a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate. Because of their unique specificity and essential role in viral polyprotein processing, these proteases are suitable targets for the development of antiviral drugs. In order to obtain near-equipotent, broad-spectrum antivirals against alphacoronaviruses, betacoronaviruses, and enteroviruses, we pursued a structure-based design of peptidomimetic α-ketoamides as inhibitors of main and 3C proteases. Six crystal structures of protease-inhibitor complexes were determined as part of this study. Compounds synthesized were tested against the recombinant proteases as well as in viral replicons and virus-infected cell cultures; most of them were not cell-toxic. Optimization of the P2 substituent of the α-ketoamides proved crucial for achieving near-equipotency against the three virus genera. The best near-equipotent inhibitors, 11u (P2 = cyclopentylmethyl) and 11r (P2 = cyclohexylmethyl), display low-micromolar EC50 values against enteroviruses, alphacoronaviruses, and betacoronaviruses in cell cultures. In Huh7 cells, 11r exhibits three-digit picomolar activity against the Middle East Respiratory Syndrome coronavirus.

Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume63
Issue number9
Pages (from-to)4562-4578
Number of pages17
ISSN0022-2623
DOIs
Publication statusPublished - 14.05.2020

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)

DFG Research Classification Scheme

  • 201-01 Biochemistry

Coronavirus related work

  • Research on SARS-CoV-2 / COVID-19

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