ArticleProceedings of the National Academy of Sciences of the United States of America2011
A macrocyclic HCV NS3/4A protease inhibitor interacts with protease and helicase residues in the complex with its full-length target.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 56 citations in OpenAlex.
- Article
- Antiviral nanomedicine: Advantages, mechanisms and advanced therapies.Bioactive materials · 2025Review
- Review
- A Novel Approach to Develop New and Potent Inhibitors for the Simultaneous Inhibition of Protease and Helicase Activities of HCV NS3/4A Protease: A Computational Approach.Molecules (Basel, Switzerland) · 2023Article
- Evaluation of interactions between the hepatitis C virus NS3/4A and sulfonamidobenzamide based molecules using molecular docking, molecular dynamics simulations and binding free energy calculations.Journal of computer-aided molecular design · 2023Article
- Characterization of a multipurpose NS3 surface patch coordinating HCV replicase assembly and virion morphogenesis.PLoS pathogens · 2022Article
- Synthesis and Applications of Nitrogen-Containing Heterocycles as Antiviral Agents.Molecules (Basel, Switzerland) · 2022Review
- A Novel Small Molecule Inhibits Hepatitis C Virus Propagation in Cell Culture.Microbiology spectrum · 2021Article
- AnJournal of biomolecular structure & dynamics · 2021Article
- Hepatitis C Virus NS3 Protease and Helicase Inhibitors from Red Sea Sponge (International journal of nanomedicine · 2020Article
- Exploring small molecules with pan-genotypic inhibitory activities against hepatitis C virus NS3/4A serine protease.Bioorganic & medicinal chemistry letters · 2019Article
- UsingACS medicinal chemistry letters · 2018Article
- Infection of Common Marmosets with GB Virus B Chimeric Virus Encoding the Major Nonstructural Proteins NS2 to NS4A of Hepatitis C Virus.Journal of virology · 2016Article
- Direct-acting antiviral agents for hepatitis C: structural and mechanistic insights.Nature reviews. Gastroenterology & hepatology · 2016Review
- Simultaneously Targeting the NS3 Protease and Helicase Activities for More Effective Hepatitis C Virus Therapy.ACS chemical biology · 2015Article
- Functional interplay among the flavivirus NS3 protease, helicase, and cofactors.Virologica Sinica · 2014Review
- Novel Peptidomimetic Hepatitis C Virus NS3/4A Protease Inhibitors Spanning the P2-P1' Region.ACS medicinal chemistry letters · 2014Article
- Molecular docking investigation of the binding interactions of macrocyclic inhibitors with HCV NS3 protease and its mutants (R155K, D168A and A156V).The protein journal · 2014Article
- Article
- The interdomain interface in bifunctional enzyme protein 3/4A (NS3/4A) regulates protease and helicase activities.Protein science : a publication of the Protein Society · 2013Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hepatitis C virus (HCV) infection is a global health burden with over 170 million people infected worldwide. In a significant portion of patients chronic hepatitis C infection leads to serious liver diseases, including fibrosis, cirrhosis, and hepatocellular carcinoma. The HCV NS3 protein is essential for viral polyprotein processing and RNA replication and hence viral replication. It is composed of an N-terminal serine protease domain and a C-terminal helicase/NTPase domain. For full activity, the protease requires the NS4A protein as a cofactor. HCV NS3/4A protease is a prime target for developing direct-acting antiviral agents. First-generation NS3/4A protease inhibitors have recently been introduced into clinical practice, markedly changing HCV treatment options. To date, crystal structures of HCV NS3/4A protease inhibitors have only been reported in complex with the protease domain alone. Here, we present a unique structure of an inhibitor bound to the full-length, bifunctional protease-helicase NS3/4A and show that parts of the P4 capping and P2 moieties of the inhibitor interact with both protease and helicase residues. The structure sheds light on inhibitor binding to the more physiologically relevant form of the enzyme and supports exploring inhibitor-helicase interactions in the design of the next generation of HCV NS3/4A protease inhibitors. In addition, small angle X-ray scattering confirmed the observed protease-helicase domain assembly in solution.
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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.