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• W2165834248 endingPage "2507" @default.
• W2165834248 startingPage "2496" @default.
• W2165834248 abstract "Although the mechanisms of action (MoA) of nonstructural protein 3 inhibitors (NS3i) and NS5B inhibitors (NS5Bi) are well understood, the MoA of cyclophilin inhibitors (CypI) and NS5A inhibitors (NS5Ai) are not fully defined. In this study, we examined whether CypI and NS5Ai interfere with hepatitis C virus (HCV) RNA synthesis of replication complexes (RCs) or with an earlier step of HCV RNA replication, the creation of double-membrane vesicles (DMVs) essential for HCV RNA replication. In contrast to NS5Bi, both CypI and NS5Ai do not block HCV RNA synthesis by way of RCs, suggesting that they exert their antiviral activity prior to the establishment of enzymatically active RCs. We found that viral replication is not a precondition for DMV formation, since the NS3-NS5B polyprotein or NS5A suffices to create DMVs. Importantly, only CypI and NS5Ai, but not NS5Bi, mir-122, or phosphatidylinositol-4 kinase IIIα (PI4KIIIα) inhibitors, prevent NS3-NS5B-mediated DMV formation. NS3-NS5B was unable to create DMVs in cyclophilin A (CypA) knockdown (KD) cells. We also found that the isomerase activity of CypA is absolutely required for DMV formation. This not only suggests that NS5A and CypA act in concert to build membranous viral factories but that CypI and NS5Ai mediate their early anti-HCV effects by preventing the formation of organelles, where HCV replication is normally initiated. This is the first investigation to examine the effect of a large panel of anti-HCV agents on DMV formation, and the results reveal that CypI and NS5Ai act at the same membranous web biogenesis step of HCV RNA replication, thus indicating a new therapeutic target of chronic hepatitis C." @default.
• W2165834248 created "2016-06-24" @default.
• W2165834248 creator A5010201985 @default.
• W2165834248 creator A5022208893 @default.
• W2165834248 creator A5022564307 @default.
• W2165834248 creator A5049620926 @default.
• W2165834248 creator A5060217430 @default.
• W2165834248 date "2015-05-01" @default.
• W2165834248 modified "2023-10-13" @default.
• W2165834248 title "Cyclophilin and NS5A Inhibitors, but Not Other Anti-Hepatitis C Virus (HCV) Agents, Preclude HCV-Mediated Formation of Double-Membrane-Vesicle Viral Factories" @default.
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• W2165834248 doi "https://doi.org/10.1128/aac.04958-14" @default.
• W2165834248 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4394764" @default.
• W2165834248 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/25666154" @default.
• W2165834248 hasPublicationYear "2015" @default.

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