Effects of NS2B-NS3 protease and furin inhibition on West Nile and Dengue virus replication

• Verfasst von: Kouretova, Jenny [VerfasserIn]
• Verfasst von: Kallis, Stephanie [VerfasserIn]
• Verfasst von: Bartenschlager, Ralf [VerfasserIn]
• Titel: Effects of NS2B-NS3 protease and furin inhibition on West Nile and Dengue virus replication
• Verf.angabe: Jenny Kouretova, M. Zouhir Hammamy, Anton Epp, Kornelia Hardes, Stephanie Kallis, Linlin Zhang, Rolf Hilgenfeld, Ralf Bartenschlager and Torsten Steinmetzer
• E-Jahr: 2017
• Jahr: 07 April 2017
• Umfang: 10 S.
• Teil: volume:32
• Teil: year:2017
• Teil: number:1
• Teil: pages:712-721
• Teil: extent:10
• Fussnoten: Gesehen am 18.10.2018
• Titel Quelle: Enthalten in: Journal of enzyme inhibition and medicinal chemistry
• Ort Quelle: Abingdon : Taylor & Francis Group, 1985
• Jahr Quelle: 2017
• Band/Heft Quelle: 32(2017), 1, Seite 712-721
• ISSN Quelle: 1475-6374
• DOI: doi:10.1080/14756366.2017.1306521
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: antiviral activity
• Sach-SW: Dengue virus
• Sach-SW: furin
• Sach-SW: NS2B-NS3 protease
• Sach-SW: West Nile virus
• K10plus-PPN: 1582065764

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-NH2 inhibits 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.