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

• Published in: Journal of enzyme inhibition and medicinal chemistry 2017-01, Vol.32 (1), p.712-721
• Main Authors: Kouretova, Jenny, Hammamy, M. Zouhir, Epp, Anton, Hardes, Kornelia, Kallis, Stephanie, Zhang, Linlin, Hilgenfeld, Rolf, Bartenschlager, Ralf, Steinmetzer, Torsten
• Format: Article
• Language: English
• Subjects: antiviral activity; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Cell culture; Dengue fever; Dengue virus; Dengue Virus - drug effects; Dengue Virus - enzymology; Dengue Virus - growth & development; Dose-Response Relationship, Drug; Furin; Furin - antagonists & inhibitors; Furin - metabolism; Microbial Sensitivity Tests; Molecular Structure; NS2B-NS3 protease; Phenylalanine; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Proteinase inhibitors; Replication; RNA Helicases - antagonists & inhibitors; RNA Helicases - metabolism; Serine Endopeptidases - metabolism; Structure-Activity Relationship; Substrate specificity; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - metabolism; Virus Replication - drug effects; West Nile virus; West Nile virus - drug effects; West Nile virus - enzymology; West Nile virus - growth & development
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2017.1306521

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-NH 2 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.