title: ACH-806, an NS4A antagonist, inhibits hepatitis C virus replication by altering the composition of viral replication complexes.
abstract: Treatment of hepatitis C patients with direct-acting antiviral drugs involves the combination of multiple small-molecule inhibitors of distinctive mechanisms of action. ACH-806 (or GS-9132) is a novel, small-molecule inhibitor specific for hepatitis C virus (HCV). It inhibits viral RNA replication in HCV replicon cells and was active in genotype 1 HCV-infected patients in a proof-of-concept clinical trial (1). Here, we describe a potential mechanism of action (MoA) wherein ACH-806 alters viral replication complex (RC) composition and function. We found that ACH-806 did not affect HCV polyprotein translation and processing, the early events of the formation of HCV RC. Instead, ACH-806 triggered the formation of a homodimeric form of NS4A with a size of 14 kDa (p14) both in replicon cells and in Huh-7 cells where NS4A was expressed alone. p14 production was negatively regulated by NS3, and its appearance in turn was associated with reductions in NS3 and, especially, NS4A content in RCs due to their accelerated degradation. A previously described resistance substitution near the N terminus of NS3, where NS3 interacts with NS4A, attenuated the reduction of NS3 and NS4A conferred by ACH-806 treatment. Taken together, we show that the compositional changes in viral RCs are associated with the antiviral activity of ACH-806. Small molecules, including ACH-806, with this novel MoA hold promise for further development and provide unique tools for clarifying the functions of NS4A in HCV replication.
authors: Department of Antiviral Drug Discovery, Achillion Pharmaceuticals, New Haven, Connecticut, USA.
authors: Wengang
authors: W
authors: Yang
authors: Yongnian
authors: Y
authors: Sun
authors: Xiaohong
authors: X
authors: Hou
authors: Yongsen
authors: Y
authors: Zhao
authors: Joanne
authors: J
authors: Fabrycki
authors: Dawei
authors: D
authors: Chen
authors: Xiangzhu
authors: X
authors: Wang
authors: Atul
authors: A
authors: Agarwal
authors: Avinash
authors: A
authors: Phadke
authors: Milind
authors: M
authors: Deshpande
authors: Mingjun
authors: M
authors: Huang
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D010670:Phenylthiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D012367:RNA, Viral / Q000096:biosynthesis; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010670:Phenylthiourea; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; C530651:1-(4-pentyloxy-3-trifluoromethylphenyl)-3-(pyridine-3-carbonyl)thiourea; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus
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