title: Evaluation of the anti-arenaviral activity of the subtilisin kexin isozyme-1/site-1 protease inhibitor PF-429242.
abstract: The cellular protease subtilisin kexin isozyme-1 (SKI-1)/site-1 protease (S1P) is implicated in the proteolytic processing of the viral envelope glycoprotein precursor (GPC) of arenaviruses, a step strictly required for production of infectious progeny. The small molecule SKI-1/S1P inhibitor PF-429242 was shown to have anti-viral activity against Old World arenaviruses. Here we extended these studies and show that PF-429242 also inhibits GPC processing and productive infection of New World arenaviruses, making PF-429242 a broadly active anti-arenaviral drug. In combination therapy, PF-429242 potentiated the anti-viral activity of ribavirin, indicating a synergism between the two drugs. A hallmark of arenaviruses is their ability to establish persistent infection in vitro and in vivo. Notably, PF-429242 was able to efficiently and rapidly clear persistent infection by arenaviruses. Interruption of drug treatment did not result in re-emergence of infection, indicating that PF-429242 treatment leads to virus extinction.
authors.affiliation: Institute of Microbiology, University Hospital Center and University of Lausanne, Lausanne, Switzerland.
authors.forename: Antonella
authors.initials: A
authors.lastname: Pasquato
authors.forename: Cylia
authors.initials: C
authors.lastname: Rochat
authors.forename: Dominique J
authors.initials: DJ
authors.lastname: Burri
authors.forename: Giulia
authors.initials: G
authors.lastname: Pasqual
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: de la Torre
authors.forename: Stefan
authors.initials: S
authors.lastname: Kunz
mesh_terms: D000595:Amino Acid Sequence; D001117:Arenaviridae Infections / Q000188:drug therapy* / Q000201:enzymology* / Q000821:virology; D018049:Arenaviruses, Old World / Q000187:drug effects* / Q000378:metabolism; D001483:Base Sequence; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008969:Molecular Sequence Data; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; C570314:PF-429242; D011759:Pyrrolidines; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C115575:membrane-bound transcription factor peptidase, site 1