PDBsum entry 6fv1

Hydrolase

PDB id: 6fv1

Contents

Protein chains

300 a.a.

Ligands

E8E ×3

GOL ×5

DMS ×2

SO4

Waters ×474

References listed in PDB file

Key reference

• Title: α-Ketoamides as broad-Spectrum inhibitors of coronavirus and enterovirus replication: structure-Based design, Synthesis, And activity assessment.
• Authors: L.Zhang, D.Lin, Y.Kusov, Y.Nian, Q.Ma, J.Wang, A.Von brunn, P.Leyssen, K.Lanko, J.Neyts, A.De wilde, E.J.Snijder, H.Liu, R.Hilgenfeld.
• Ref.: J Med Chem, 2020, 63, 4562-4578. [DOI no: 10.1021/acs.jmedchem.9b01828]
• PubMed id: 32045235

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.