ArticleJournal of virology2007
Switching the substrate specificity of the two-component NS2B-NS3 flavivirus proteinase by structure-based mutagenesis.
Article in Journal of virology, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 54 citations in OpenAlex.
- Development of Lipopeptides as Orthoflavivirin Inhibitors with Low Micromolar Broad-Spectrum Antiorthoflaviviral Activity.Journal of medicinal chemistry · 2025Article
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- Dengue virus NS4B protein as a target for developing antivirals.Frontiers in cellular and infection microbiology · 2022Review
- Review
- Structure-Based Macrocyclization of Substrate Analogue NS2B-NS3 Protease Inhibitors of Zika, West Nile and Dengue viruses.ChemMedChem · 2020Article
- Determinants of duck Tembusu virus NS2A/2B polyprotein procession attenuated viral replication and proliferation in vitro.Scientific reports · 2020Article
- Insights into Structures and Dynamics of Flavivirus Proteases from NMR Studies.International journal of molecular sciences · 2020Review
- Effects of NS2B-NS3 protease and furin inhibition on West Nile and Dengue virus replication.Journal of enzyme inhibition and medicinal chemistry · 2017Article
- Context-Dependent Cleavage of the Capsid Protein by the West Nile Virus Protease Modulates the Efficiency of Virus Assembly.Journal of virology · 2015Article
- Biochemical characterization of recombinant Enterovirus 71 3C protease with fluorogenic model peptide substrates and development of a biochemical assay.Antimicrobial agents and chemotherapy · 2015Article
- High-resolution analysis and functional mapping of cleavage sites and substrate proteins of furin in the human proteome.PloS one · 2013Article
- Enzymatic analysis of recombinant Japanese encephalitis virus NS2B(H)-NS3pro protease with fluorogenic model peptide substrates.PloS one · 2012Article
- Ligand-bound structures of the dengue virus protease reveal the active conformation.Journal of virology · 2012Article
- New details of HCV NS3/4A proteinase functionality revealed by a high-throughput cleavage assay.PloS one · 2012Article
- Article
- Structure-guided fragment-based in silico drug design of dengue protease inhibitors.Journal of computer-aided molecular design · 2011Article
- Virtual ligand screening of the National Cancer Institute (NCI) compound library leads to the allosteric inhibitory scaffolds of the West Nile Virus NS3 proteinase.Assay and drug development technologies · 2011Article
- Structural and functional parameters of the flaviviral protease: a promising antiviral drug target.Future virology · 2010Article
- Structure-guided mutagenesis of active site residues in the dengue virus two-component protease NS2B-NS3.Journal of biomedical science · 2010Article
- Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
The flavivirus NS2B-NS3(pro)teinase is an essential element in the proteolytic processing of the viral precursor polyprotein and therefore a potential drug target. Recently, crystal structures and substrate preferences of NS2B-NS3pro from Dengue and West Nile viruses (DV and WNV) were determined. We established that the presence of Gly-Gly at the P1'-P2' positions is optimal for cleavage by WNV NS3pro, whereas DV NS3pro tolerates well the presence of bulky residues at either P1' or P2'. Structure-based modeling suggests that Arg(76) and Pro(131)-Thr(132) limit the P1'-P2' subsites and restrict the cleavage preferences of the WNV enzyme. In turn, Leu(76) and Lys(131)-Pro(132) widen the specificity of DV NS3pro. Guided by these structural models, we expressed and purified mutant WNV NS2B-NS3pro and evaluated cleavage preferences by using positional scanning of the substrate peptides in which the P4-P1 and the P3'-P4' positions were fixed and the P1' and P2' positions were each randomized. We established that WNV R76L and P131K-T132P mutants acquired DV-like cleavage preferences, whereas T52V had no significant effect. Our work is the first instance of engineering a viral proteinase with switched cleavage preferences and should provide valuable data for the design of optimized substrates and substrate-based selective inhibitors of flaviviral proteinases.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.