6FV1

Structure of human coronavirus NL63 main protease in complex with the alpha-ketoamide (S)-N-((S)-4-(benzylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2-cinnamamido-4-methylpentanamide (cinnamoyl-leucine-GlnLactam-CO-CO-NH-benzyl)

Summary for 6FV1

• Entry DOI: 10.2210/pdb6fv1/pdb
• Descriptor: 3C-like proteinase, (2~{S})-4-methyl-~{N}-[(2~{S},3~{R})-3-oxidanyl-4-oxidanylidene-1-[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]-4-[(phenylmethyl)amino]butan-2-yl]-2-[[(~{E})-3-phenylprop-2-enoyl]amino]pentanamide, GLYCEROL, ... (6 entities in total)
• Functional Keywords: viral protease, coronavirus, alpha-ketoamide, inhibitor, hydrolase
• Biological source: Human coronavirus NL63 (HCoV-NL63)
• Total number of polymer chains: 3
• Total formula weight: 101954.44

Authors

Zhang, L.,Hilgenfeld, R. (deposition date: 2018-02-28, release date: 2019-03-20, Last modification date: 2024-11-06)

Primary citation

Zhang, L.,Lin, D.,Kusov, Y.,Nian, Y.,Ma, Q.,Wang, J.,von Brunn, A.,Leyssen, P.,Lanko, K.,Neyts, J.,de Wilde, A.H.,Snijder, E.J.,Liu, H.,Hilgenfeld, R.
Alpha-ketoamides as broad-spectrum inhibitors of coronavirus and enterovirus replication Structure-based design, synthesis, and activity assessment.
J.Med.Chem., 2020

PubMed 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, (P2 = cyclopentylmethyl) and (P2 = cyclohexylmethyl), display low-micromolar EC values against enteroviruses, alphacoronaviruses, and betacoronaviruses in cell cultures. In Huh7 cells, exhibits three-digit picomolar activity against the Middle East Respiratory Syndrome coronavirus.

PubMed: 32045235
DOI: 10.1021/acs.jmedchem.9b01828

Experimental method

X-RAY DIFFRACTION (2.3 Å)