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Quaternary Structure, Substrate Selectivity and Inhibitor Design for SARS 3C-Like Proteinase
- Source :
- Current Pharmaceutical Design. 12:4555-4564
- Publication Year :
- 2006
- Publisher :
- Bentham Science Publishers Ltd., 2006.
-
Abstract
- The SARS coronavirus 3C-like proteinase is recognized as a potential drug design target for the treatment of severe acute respiratory syndrome. In the past few years, much work has been done to understand the catalytic mechanism of this target protein and to design its selective inhibitors. The protein exists as a dimer/monomer mixture in solution and the dimer was confirmed to be the active species for the enzyme reaction. Quantitative dissociation constants have been reported for the dimer by using analytic ultracentrifuge, gel filtration and enzyme assays. Though the enzyme is a cysteine protease with a chymotrypsin fold, SARS 3C-like proteinase follows the general base catalytic mechanism similar to chymotrypsin. As the enzyme can cut eleven different sites on the viral polyprotein, the substrate specificity has been studied by synthesized peptides corresponding or similar to the cleavage sites on the polyprotein. Predictive model was built for substrate structure and activity relationships and can be applied in inhibitor design. Due to the lack of potential drugs for the treatment of SARS, the discovery of inhibitors against SARS 3C-like proteinase, which can potentially be optimized as drugs appears to be highly desirable. Various groups have been working on inhibitor discovery by virtual screening, compound library screening, modification of existing compounds or natural products. High-throughput in vitro assays, auto-cleavage assays and viral replication assays have been developed for inhibition activity tests. Inhibitors with IC50 values as low as 60 nM have been reported.
- Subjects :
- Stereochemistry
Drug Evaluation, Preclinical
Biology
medicine.disease_cause
Antiviral Agents
Substrate Specificity
Structure-Activity Relationship
Viral Proteins
Catalytic Domain
Drug Discovery
medicine
Animals
Humans
Structure–activity relationship
Protease Inhibitors
Protein Structure, Quaternary
Coronavirus 3C Proteases
Coronavirus
Pharmacology
chemistry.chemical_classification
Virtual screening
Chymotrypsin
Dose-Response Relationship, Drug
Cysteine protease
Cysteine Endopeptidases
Enzyme
Models, Chemical
Severe acute respiratory syndrome-related coronavirus
Biochemistry
chemistry
Enzyme inhibitor
Drug Design
biology.protein
Computer-Aided Design
Target protein
Subjects
Details
- ISSN :
- 13816128
- Volume :
- 12
- Database :
- OpenAIRE
- Journal :
- Current Pharmaceutical Design
- Accession number :
- edsair.doi.dedup.....650cd7bf8409f998400b9395e352de3f