ArticleJournal of virology2012
A conserved tandem cyclophilin-binding site in hepatitis C virus nonstructural protein 5A regulates Alisporivir susceptibility.
Article in Journal of virology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed.
- Cyclophilin A: promising target in cancer therapy.Cancer biology & therapy · 2024Review
- MxB Disrupts Hepatitis C Virus NS5A-CypA Complex: Insights From a Combined Theoretical and Experimental Approach.Frontiers in microbiology · 2022Article
- The Inherent Dynamics and Interaction Sites of the SARS-CoV-2 Nucleocapsid N-Terminal Region.Journal of molecular biology · 2021Article
- Cyclophilins and Their Roles in Hepatitis C Virus and Flavivirus Infections: Perspectives for Novel Antiviral Approaches.Pathogens (Basel, Switzerland) · 2021Review
- ISGylation of Hepatitis C Virus NS5A Protein Promotes Viral RNA Replication via Recruitment of Cyclophilin A.Journal of virology · 2020Article
- Cyclophilin A allows the allosteric regulation of a structural motif in the disordered domain 2 of NS5A and thereby fine-tunes HCV RNA replication.The Journal of biological chemistry · 2019Article
- Differences across cyclophilin A orthologs contribute to the host range restriction of hepatitis C virus.eLife · 2019Article
- NMR reveals the intrinsically disordered domain 2 of NS5A protein as an allosteric regulator of the hepatitis C virus RNA polymerase NS5B.The Journal of biological chemistry · 2017Article
- Chaperones in hepatitis C virus infection.World journal of hepatology · 2016Review
- Characterization of the Anti-HCV Activities of the New Cyclophilin Inhibitor STG-175.PloS one · 2016Article
- The role of immunophilins in viral infection.Biochimica et biophysica acta · 2015Article
- A Proline-Tryptophan Turn in the Intrinsically Disordered Domain 2 of NS5A Protein Is Essential for Hepatitis C Virus RNA Replication.The Journal of biological chemistry · 2015Article
- Hepatitis C virus RNA replication depends on specific cis- and trans-acting activities of viral nonstructural proteins.PLoS pathogens · 2015Article
- Intrinsic disorder mediates hepatitis C virus core-host cell protein interactions.Protein science : a publication of the Protein Society · 2015Article
- Should NS5A inhibitors serve as the scaffold for all-oral anti-HCV combination therapies?Hepatic medicine : evidence and research · 2015Review
- The Novel Cyclophilin Inhibitor CPI-431-32 Concurrently Blocks HCV and HIV-1 Infections via a Similar Mechanism of Action.PloS one · 2015Article
- Inhibitors of peptidyl proline isomerases as antivirals in hepatitis C and other viruses.PLoS pathogens · 2014Review
- Hepatitis C NS5A protein: two drug targets within the same protein with different mechanisms of resistance.Current opinion in virology · 2014Review
- The combination of alisporivir plus an NS5A inhibitor provides additive to synergistic anti-hepatitis C virus activity without detectable cross-resistance.Antimicrobial agents and chemotherapy · 2014Article
- Cyclophilins as modulators of viral replication.Viruses · 2013Review
Corrections and comments
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Authors and funding
4 authors.
Funding
Abstract
Cyclophilin A (CyPA) and its peptidyl-prolyl isomerase (PPIase) activity play an essential role in hepatitis C virus (HCV) replication, and mounting evidence indicates that nonstructural protein 5A (NS5A) is the major target of CyPA. However, neither a consensus CyPA-binding motif nor specific proline substrates that regulate CyPA dependence and sensitivity to cyclophilin inhibitors (CPIs) have been defined to date. We systematically characterized all proline residues in NS5A domain II, low-complexity sequence II (LCS-II), and domain III with both biochemical binding and functional replication assays. A tandem cyclophilin-binding site spanning domain II and LCS-II was identified. The first site contains a consensus sequence motif of AØPXW (where Ø is a hydrophobic residue) that is highly conserved in the majority of the genotypes of HCV (six of seven; the remaining genotype has VØPXW). The second tandem site contains a similar motif, and the ØP sequence is again conserved in six of the seven genotypes. Consistent with the similarity of their sequences, peptides representing the two binding motifs competed for CyPA binding in a spot-binding assay and induced similar chemical shifts when bound to the active site of CyPA. The two prolines (P310 and P341 of Japanese fulminant hepatitis 1 [JFH-1]) contained in these motifs, as well as a conserved tryptophan in the spacer region, were required for CyPA binding, HCV replication, and CPI resistance. Together, these data provide a high-resolution mapping of proline residues important for CyPA binding and identify critical amino acids modulating HCV susceptibility to the clinical CPI Alisporivir.
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