6WTK

Target information

RCSB PDB
6WTK
Title
Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication
Method
X-RAY DIFFRACTION
Resolution
2
Classification
Hydrolase/Hydrolase Inhibitor
Organism
Severe acute respiratory syndrome coronavirus 2
Protein
Replicase polyprotein 1ab (P0DTD1)    Looking for covalent inhibitors of this target ?
Year
2020
Publication Title
Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication.
Abstract

The main protease, M pro (or 3CL pro ) in SARS-CoV-2 is a viable drug target because of its essential role in the cleavage of the virus polypeptide. Feline infectious peritonitis, a fatal coronavirus infection in cats, was successfully treated previously with a prodrug GC376, a dipeptide-based protease inhibitor. Here, we show the prodrug and its parent GC373, are effective inhibitors of the M pro from both SARS-CoV and SARS-CoV-2 with IC 50 values in the nanomolar range. Crystal structures of SARS-CoV-2 M pro with these inhibitors have a covalent modification of the nucleophilic Cys145. NMR analysis reveals that inhibition proceeds via reversible formation of a hemithioacetal. GC373 and GC376 are potent inhibitors of SARS-CoV-2 replication in cell culture. They are strong drug candidates for the treatment of human coronavirus infections because they have already been successful in animals. The work here lays the framework for their use in human trials for the treatment of COVID-19.

External Link
RCSB PDB





Ligand information

HET
UED
Chain ID
A
HET Number
401
Molecular Formula
C21H31N3O8S
Structure
2D structure
IUPAC Name
(1S,2S)-2-[[(2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoyl]amino]-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid
InChI
InChI=1S/C21H31N3O8S/c1-13(2)10-16(24-21(28)32-12-14-6-4-3-5-7-14)19(26)23-17(20(27)33(29,30)31)11-15-8-9-22-18(15)25/h3-7,13,15-17,20,27H,8-12H2,1-2H3,(H,22,25)(H,23,26)(H,24,28)(H,29,30,31)/t15-,16-,17-,20-/m0/s1
InChI Key
BSPZFJDYQHDZNR-BOSXTWCSSA-N
Canonical SMILES
CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C[C@@H]1CCNC1=O)[C@@H](O)S(O)(=O)=O
Bioactivity data
CI006853

Covalent Binding

Warhead
Sulfonic acid
Reaction Mechanism
Nucleophilic Substitution
Residue
CYS : 145
Residue Chain
A
Interactions
Pharmacophore Model