title: Inhibitory effect of presenilin inhibitor LY411575 on maturation of hepatitis C virus core protein, production of the viral particle and expression of host proteins involved in pathogenicity.
abstract: Hepatitis C virus (HCV) core protein is responsible for the formation of infectious viral particles and induction of pathogenicity. The C-terminal transmembrane region of the immature core protein is cleaved by signal peptide peptidase (SPP) for maturation of the core protein. SPP belongs to the family of presenilin-like aspartic proteases. Some presenilin inhibitors are expected to suppress HCV infection and production; however, this anti-HCV effect has not been investigated in detail. In this study, presenilin inhibitors were screened to identify anti-HCV compounds. Of the 13 presenilin inhibitors tested, LY411575 was the most potent inhibitor of SPP-dependent cleavage of HCV core protein. Production of intracellular core protein and supernatant infectious viral particles from HCV-infected cells was significantly impaired by LY411575 in a dose-dependent manner (half maximum inhibitory concentration = 0.27 μM, cytotoxic concentration of the extracts to cause death to 50% of viable cells > 10 μM). No effect of LY411575 on intracellular HCV RNA in the subgenomic replicon cells was detected. LY411575 synergistically promoted daclatasvir-dependent inhibition of viral production, but not that of viral replication. Furthermore, LY411575 inhibited HCV-related production of reactive oxygen species and expression of NADPH oxidases and vascular endothelial growth factor. Taken together, our data suggest that LY411575 suppresses HCV propagation through SPP inhibition and impairs host gene expressions related to HCV pathogenicity.
authors: Department of Microbiology, Graduate School of Medical Science, University of Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi 409-3898, Japan.
authors: Teruhime
authors: T
authors: Otoguro
authors: Department of Microbiology, Graduate School of Medical Science, University of Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi 409-3898, Japan.
authors: Tomohisa
authors: T
authors: Tanaka
authors: Department of Microbiology, Graduate School of Medical Science, University of Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi 409-3898, Japan.
authors: Hirotake
authors: H
authors: Kasai
authors: Department of Microbiology, Graduate School of Medical Science, University of Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi 409-3898, Japan.
authors: Atsuya
authors: A
authors: Yamashita
authors: Department of Microbiology, Graduate School of Medical Science, University of Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi 409-3898, Japan.
authors: Kohji
authors: K
authors: Moriishi
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology; D001381:Azepines / Q000494:pharmacology*; D002219:Carbamates; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D004357:Drug Synergism; D005786:Gene Expression Regulation; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology*; D006526:Hepatitis C / Q000235:genetics* / Q000378:metabolism / Q000821:virology*; D054884:Host-Pathogen Interactions; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D053763:Presenilins / Q000037:antagonists & inhibitors / Q000378:metabolism; D059748:Proteolysis; D011759:Pyrrolidines; D017382:Reactive Oxygen Species / Q000378:metabolism; D014633:Valine / Q000031:analogs & derivatives; D014758:Viral Core Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D001381:Azepines; D002219:Carbamates; D007093:Imidazoles; C484278:N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; D053763:Presenilins; D011759:Pyrrolidines; D017382:Reactive Oxygen Species; D014758:Viral Core Proteins; D014633:Valine; C549273:daclatasvir; D000409:Alanine
keywords: LY411575; core protein; hepatitis C virus; signal peptide peptidase