Article: article from journal or magazin.
Evaluation of the anti-arenaviral activity of the subtilisin kexin isozyme-1/site-1 protease inhibitor PF-429242.
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.
Amino Acid Sequence, Arenaviridae Infections/drug therapy, Arenaviridae Infections/enzymology, Arenaviruses, Old World/drug effects, Arenaviruses, Old World/metabolism, Base Sequence, Cell Line, Enzyme Inhibitors/pharmacology, Humans, Molecular Sequence Data, Proprotein Convertases/antagonists & inhibitors, Proprotein Convertases/genetics, Pyrrolidines/pharmacology, Serine Endopeptidases/genetics, Serine Endopeptidases/metabolism
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