ArticlePloS one2013
Allosteric inhibitors of the NS3 protease from the hepatitis C virus.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
15 citing papers in PubMed, 33 citations in OpenAlex.
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- Utilizing sinapic acid as an inhibitory antiviral agent against MERS-CoV PLpro.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2024Article
- VSpipe-GUI, an Interactive Graphical User Interface for Virtual Screening and Hit Selection.International journal of molecular sciences · 2024Article
- Identification of Doxorubicin as Repurposing Inhibitory Drug for MERS-CoV PLpro.Molecules (Basel, Switzerland) · 2022Article
- Repositioning small molecule drugs as allosteric inhibitors of the BFT-3 toxin from enterotoxigenic Bacteroides fragilis.Protein science : a publication of the Protein Society · 2022Article
- In Vitro Antiviral Activity of Tyrosinase from MushroomPharmaceuticals (Basel, Switzerland) · 2021Article
- Rutin Is a Low Micromolar Inhibitor of SARS-CoV-2 Main Protease 3CLpro: Implications for Drug Design of Quercetin Analogs.Biomedicines · 2021Article
- Structural stability of SARS-CoV-2 3CLpro and identification of quercetin as an inhibitor by experimental screening.International journal of biological macromolecules · 2020Article
- Janus Dendrimers to Assess the Anti-HCV Activity of Molecules in Cell-Assays.Pharmaceutics · 2020Article
- The role of nanotechnology in the treatment of viral infections.Therapeutic advances in infectious disease · 2017Review
- Identification of a Drug Targeting an Intrinsically Disordered Protein Involved in Pancreatic Adenocarcinoma.Scientific reports · 2017Article
- Benzbromarone, Quercetin, and Folic Acid Inhibit Amylin Aggregation.International journal of molecular sciences · 2016Article
- Structural and Thermodynamic Effects of Macrocyclization in HCV NS3/4A Inhibitor MK-5172.ACS chemical biology · 2016Article
- Rescuing compound bioactivity in a secondary cell-based screening by using γ-cyclodextrin as a molecular carrier.International journal of nanomedicine · 2015Article
- Post-translational modifications of hepatitis C viral proteins and their biological significance.World journal of gastroenterology · 2013Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The nonstructural protein 3 (NS3) from the hepatitis C virus processes the non-structural region of the viral precursor polyprotein in infected hepatic cells. The NS3 protease activity has been considered a target for drug development since its identification two decades ago. Although specific inhibitors have been approved for clinical therapy very recently, resistance-associated mutations have already been reported for those drugs, compromising their long-term efficacy. Therefore, there is an urgent need for new anti-HCV agents with low susceptibility to resistance-associated mutations. Regarding NS3 protease, two strategies have been followed: competitive inhibitors blocking the active site and allosteric inhibitors blocking the binding of the accessory viral protein NS4A. In this work we exploit the intrinsic Zn(+2)-regulated plasticity of the protease to identify a new type of allosteric inhibitors. In the absence of Zn(+2), the NS3 protease adopts a partially-folded inactive conformation. We found ligands binding to the Zn(+2)-free NS3 protease, trap the inactive protein, and block the viral life cycle. The efficacy of these compounds has been confirmed in replicon cell assays. Importantly, direct calorimetric assays reveal a low impact of known resistance-associated mutations, and enzymatic assays provide a direct evidence of their inhibitory activity. They constitute new low molecular-weight scaffolds for further optimization and provide several advantages: 1) new inhibition mechanism simultaneously blocking substrate and cofactor interactions in a non-competitive fashion, appropriate for combination therapy; 2) low impact of known resistance-associated mutations; 3) inhibition of NS4A binding, thus blocking its several effects on NS3 protease.
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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.