4DCD

1.6A resolution structure of PolioVirus 3C Protease Containing a covalently bound dipeptidyl inhibitor

Summary for 4DCD

• Entry DOI: 10.2210/pdb4dcd/pdb
• Related: 3UR6 3UR9 4F49
• Descriptor: Genome polyprotein, 2,3-DIHYDROXY-1,4-DITHIOBUTANE, (1S,2S)-2-({N-[(benzyloxy)carbonyl]-L-leucyl}amino)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid, ... (5 entities in total)
• Functional Keywords: protease, poliovirus, antiviral inhibitors, dipeptidyl inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human poliovirus 1
• Total number of polymer chains: 1
• Total formula weight: 21439.32

Authors

Lovell, S.,Battaile, K.P.,Kim, Y.,Tiew, K.-C.,Mandadapu, S.R.,Alliston, K.R.,Groutas, W.C.,Chang, K.O. (deposition date: 2012-01-17, release date: 2012-09-05, Last modification date: 2024-10-30)

Primary citation

Kim, Y.,Lovell, S.,Tiew, K.C.,Mandadapu, S.R.,Alliston, K.R.,Battaile, K.P.,Groutas, W.C.,Chang, K.O.
Broad-Spectrum Antivirals against 3C or 3C-Like Proteases of Picornaviruses, Noroviruses, and Coronaviruses.
J.Virol., 86:11754-11762, 2012

PubMed Abstract: Phylogenetic analysis has demonstrated that some positive-sense RNA viruses can be classified into the picornavirus-like supercluster, which includes picornaviruses, caliciviruses, and coronaviruses. These viruses possess 3C or 3C-like proteases (3Cpro or 3CLpro, respectively), which contain a typical chymotrypsin-like fold and a catalytic triad (or dyad) with a Cys residue as a nucleophile. The conserved key sites of 3Cpro or 3CLpro may serve as attractive targets for the design of broad-spectrum antivirals for multiple viruses in the supercluster. We previously reported the structure-based design and synthesis of potent protease inhibitors of Norwalk virus (NV), a member of the Caliciviridae family. We report herein the broad-spectrum antiviral activities of three compounds possessing a common dipeptidyl residue with different warheads, i.e., an aldehyde (GC373), a bisulfite adduct (GC376), and an α-ketoamide (GC375), against viruses that belong to the supercluster. All compounds were highly effective against the majority of tested viruses, with half-maximal inhibitory concentrations in the high nanomolar or low micromolar range in enzyme- and/or cell-based assays and with high therapeutic indices. We also report the high-resolution X-ray cocrystal structures of NV 3CLpro-, poliovirus 3Cpro-, and transmissible gastroenteritis virus 3CLpro- GC376 inhibitor complexes, which show the compound covalently bound to a nucleophilic Cys residue in the catalytic site of the corresponding protease. We conclude that these compounds have the potential to be developed as antiviral therapeutics aimed at a single virus or multiple viruses in the picornavirus-like supercluster by targeting 3Cpro or 3CLpro.

PubMed: 22915796
DOI: 10.1128/JVI.01348-12

Experimental method

X-RAY DIFFRACTION (1.69 Å)