Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp3 papain-like protease.
Adenosine Monophosphate
/ analogs & derivatives
Alanine
/ analogs & derivatives
Aniline Compounds
/ pharmacology
Animals
Antiviral Agents
/ chemistry
Benzamides
/ pharmacology
Chlorocebus aethiops
Coronavirus Papain-Like Proteases
/ antagonists & inhibitors
Drug Evaluation, Preclinical
Drug Synergism
Enzyme Assays
Flavins
/ pharmacology
Fluorescence Resonance Energy Transfer
Furans
/ pharmacology
High-Throughput Screening Assays
Inhibitory Concentration 50
Naphthalenes
/ pharmacology
Phenanthrenes
/ pharmacology
Quinones
/ pharmacology
Reproducibility of Results
SARS-CoV-2
/ drug effects
Small Molecule Libraries
/ chemistry
Vero Cells
Virus Replication
/ drug effects
COVID-19
coronavirus
protease
ubiquitin
Journal
The Biochemical journal
ISSN: 1470-8728
Titre abrégé: Biochem J
Pays: England
ID NLM: 2984726R
Informations de publication
Date de publication:
16 07 2021
16 07 2021
Historique:
received:
06
04
2021
revised:
05
05
2021
accepted:
07
06
2021
entrez:
1
7
2021
pubmed:
2
7
2021
medline:
9
7
2021
Statut:
ppublish
Résumé
The COVID-19 pandemic has emerged as the biggest life-threatening disease of this century. Whilst vaccination should provide a long-term solution, this is pitted against the constant threat of mutations in the virus rendering the current vaccines less effective. Consequently, small molecule antiviral agents would be extremely useful to complement the vaccination program. The causative agent of COVID-19 is a novel coronavirus, SARS-CoV-2, which encodes at least nine enzymatic activities that all have drug targeting potential. The papain-like protease (PLpro) contained in the nsp3 protein generates viral non-structural proteins from a polyprotein precursor, and cleaves ubiquitin and ISG protein conjugates. Here we describe the expression and purification of PLpro. We developed a protease assay that was used to screen a custom compound library from which we identified dihydrotanshinone I and Ro 08-2750 as compounds that inhibit PLpro in protease and isopeptidase assays and also inhibit viral replication in cell culture-based assays.
Identifiants
pubmed: 34198325
pii: 229150
doi: 10.1042/BCJ20210244
pmc: PMC8286840
doi:
Substances chimiques
2,3,4,10-tetrahydro-7,10-dimethyl-2,4-dioxobenzo(g)pteridine
0
5-amino-2-methyl-N-((R)-1-(1-naphthyl)ethyl)benzamide
0
Aniline Compounds
0
Antiviral Agents
0
Benzamides
0
Flavins
0
Furans
0
Naphthalenes
0
Phenanthrenes
0
Quinones
0
Small Molecule Libraries
0
remdesivir
3QKI37EEHE
Adenosine Monophosphate
415SHH325A
dihydrotanshinone I
562G9360V6
Coronavirus Papain-Like Proteases
EC 3.4.22.2
papain-like protease, SARS-CoV-2
EC 3.4.22.2
Alanine
OF5P57N2ZX
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
2517-2531Subventions
Organisme : Medical Research Council
ID : MC_UU_00018/4
Pays : United Kingdom
Informations de copyright
© 2021 The Author(s).
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