title: Effects of NS2B-NS3 protease and furin inhibition on West Nile and Dengue virus replication.
abstract: West Nile virus (WNV) and Dengue virus (DENV) replication depends on the viral NS2B-NS3 protease and the host enzyme furin, which emerged as potential drug targets. Modification of our previously described WNV protease inhibitors by basic phenylalanine analogs provided compounds with reduced potency against the WNV and DENV protease. In a second series, their decarboxylated P1-trans-(4-guanidino)cyclohexylamide was replaced by an arginyl-amide moiety. Compound 4-(guanidinomethyl)-phenylacetyl-Lys-Lys-Arg-NH2inhibits the NS2B-NS3 protease of WNV with an inhibition constant of 0.11 µM. Due to the similarity in substrate specificity, we have also tested the potency of our previously described multibasic furin inhibitors. Their further modification provided chimeric inhibitors with additional potency against the WNV and DENV proteases. A strong inhibition of WNV and DENV replication in cell culture was observed for the specific furin inhibitors, which reduced virus titers up to 10,000-fold. These studies reveal that potent inhibitors of furin can block the replication of DENV and WNV.
authors.affiliation: a Department of Pharmacy, Institute of Pharmaceutical Chemistry , Philipps University , Marburg , Germany.|b German Center for Infection Research (DZIF) , University of Marburg , Marburg , Germany.
authors.forename: Jenny
authors.initials: J
authors.lastname: Kouretova
authors.affiliation: a Department of Pharmacy, Institute of Pharmaceutical Chemistry , Philipps University , Marburg , Germany.
authors.forename: M Zouhir
authors.initials: MZ
authors.lastname: Hammamy
authors.affiliation: a Department of Pharmacy, Institute of Pharmaceutical Chemistry , Philipps University , Marburg , Germany.
authors.forename: Anton
authors.initials: A
authors.lastname: Epp
authors.affiliation: a Department of Pharmacy, Institute of Pharmaceutical Chemistry , Philipps University , Marburg , Germany.
authors.forename: Kornelia
authors.initials: K
authors.lastname: Hardes
authors.affiliation: c Department of Infectious Diseases, Molecular Virology , Heidelberg University , Heidelberg , Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kallis
authors.affiliation: d Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck , Lübeck , Germany.|e German Center for Infection Research (DZIF) , University of Lübeck , Lübeck , Germany.
authors.forename: Linlin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: d Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck , Lübeck , Germany.|e German Center for Infection Research (DZIF) , University of Lübeck , Lübeck , Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Hilgenfeld
authors.affiliation: c Department of Infectious Diseases, Molecular Virology , Heidelberg University , Heidelberg , Germany.|f German Center for Infection Research (DZIF) , Heidelberg University , Heidelberg , Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Bartenschlager
authors.affiliation: a Department of Pharmacy, Institute of Pharmaceutical Chemistry , Philipps University , Marburg , Germany.|b German Center for Infection Research (DZIF) , University of Marburg , Marburg , Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Steinmetzer
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003716:Dengue Virus / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D004305:Dose-Response Relationship, Drug; D045683:Furin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020365:RNA Helicases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*; D014902:West Nile virus / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D045683:Furin; D011480:Protease Inhibitors; D020365:RNA Helicases; D012697:Serine Endopeptidases; D017361:Viral Nonstructural Proteins; C080102:NS2B protein, flavivirus; C060028:NS3 protein, flavivirus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
keywords: Dengue virus; NS2B-NS3 protease; West Nile virus; antiviral activity; furin