title: SKI-1/S1P inhibitor PF-429242 impairs the onset of HCV infection.
abstract: Worldwide, approximately 170 million individuals are afflicted with chronic hepatitis C virus (HCV) infection. To prevent the development of inherent diseases such as cirrhosis and hepatocellular carcinoma, tremendous efforts have been made, leading to the development of promising new treatments. However, their efficiency is still dependent on the viral genotype. Additionally, these treatments that target the virus directly can trigger the emergence of resistant variants. In a previous study, we have demonstrated that a long-term (72h) inhibition of SKI-1/S1P, a master lipogenic pathway regulator through activation of SREBP, resulted in impaired HCV genome replication and infectious virion secretion. In the present study, we sought to investigate the antiviral effect of the SKI-1/S1P small molecule inhibitor PF-429242 at the early steps of the HCV lifecycle. Our results indicate a very potent antiviral effect of the inhibitor early in the viral lifecycle and that the overall action of the compound relies on two different contributions. The first one is SREBP/SKI-1/S1P dependent and involves LDLR and NPC1L1 proteins, while the second one is SREBP independent. Overall, our study confirms that SKI-1/S1P is a relevant target to impair HCV infection and that PF-429242 could be a promising candidate in the field of HCV infection treatment.
authors.affiliation: INRS-Institut Armand-Frappier, Institut National de la Recherche Scientifique, Laval, Canada.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Blanchet
authors.affiliation: Institut National de la Transfusion Sanguine, Paris, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Sureau
authors.affiliation: INRS-Institut Armand-Frappier, Institut National de la Recherche Scientifique, Laval, Canada.
authors.forename: Carl
authors.initials: C
authors.lastname: Guévin
authors.affiliation: Laboratory of Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal, Affiliated to the Université de Montréal, Montréal, Canada.
authors.forename: Nabil G
authors.initials: NG
authors.lastname: Seidah
authors.affiliation: INRS-Institut Armand-Frappier, Institut National de la Recherche Scientifique, Laval, Canada. Electronic address: patrick.labonte@iaf.inrs.ca.
authors.forename: Patrick
authors.initials: P
authors.lastname: Labonté
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology*; D011973:Receptors, LDL / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D020860:Subtilisin / Q000037:antagonists & inhibitors / Q000378:metabolism; D014771:Virion / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; C573412:LDLR protein, human; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C410800:NPC1L1 protein, human; C570314:PF-429242; D011759:Pyrrolidines; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C115575:membrane-bound transcription factor peptidase, site 1; D020860:Subtilisin
keywords: HCV; LDLR; PF-429242; SKI-1/S1P; SREBP; Viral entry