title: Novel dengue virus NS2B/NS3 protease inhibitors.
abstract: Dengue fever is a severe, widespread, and neglected disease with more than 2 million diagnosed infections per year. The dengue virus NS2B/NS3 protease (PR) represents a prime target for rational drug design. At the moment, there are no clinical PR inhibitors (PIs) available. We have identified diaryl (thio)ethers as candidates for a novel class of PIs. Here, we report the selective and noncompetitive inhibition of the serotype 2 and 3 dengue virus PR in vitro and in cells by benzothiazole derivatives exhibiting 50% inhibitory concentrations (IC50s) in the low-micromolar range. Inhibition of replication of DENV serotypes 1 to 3 was specific, since all substances influenced neither hepatitis C virus (HCV) nor HIV-1 replication. Molecular docking suggests binding at a specific allosteric binding site. In addition to the in vitro assays, a cell-based PR assay was developed to test these substances in a replication-independent way. The new compounds inhibited the DENV PR with IC50s in the low-micromolar or submicromolar range in cells. Furthermore, these novel PIs inhibit viral replication at submicromolar concentrations.
authors.affiliation: Institut für Pharmazie und Biochemie, Johannes Gutenberg-Universität, Mainz, Germany.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Wu
authors.affiliation: Institut für Virologie und Immunbiologie, Julius-Maximilians-Universität, Würzburg, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Bock
authors.affiliation: Institut für Virologie und Immunbiologie, Julius-Maximilians-Universität, Würzburg, Germany.
authors.forename: Mariya
authors.initials: M
authors.lastname: Snitko
authors.affiliation: Institut für Pharmazie und Biochemie, Johannes Gutenberg-Universität, Mainz, Germany.
authors.forename: Thilo
authors.initials: T
authors.lastname: Berger
authors.affiliation: Institut für Pharmazie und Biochemie, Johannes Gutenberg-Universität, Mainz, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Weidner
authors.affiliation: Institut für Pharmazie und Biochemie, Johannes Gutenberg-Universität, Mainz, Germany.
authors.forename: Steven
authors.initials: S
authors.lastname: Holloway
authors.affiliation: Institut für Pharmazeutische Chemie, Philipps-Universität, Marburg, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Kanitz
authors.affiliation: Institut für Pharmazeutische Chemie, Philipps-Universität, Marburg, Germany.
authors.forename: Wibke E
authors.initials: WE
authors.lastname: Diederich
authors.affiliation: LOEWE-Zentrum für Synthetische Mikrobiologie, Philipps-Universität, Marburg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Steuber
authors.affiliation: Institut für Physikalische und Theoretische Chemie, Julius-Maximilians-Universität, Würzburg, Germany.
authors.forename: Christof
authors.initials: C
authors.lastname: Walter
authors.affiliation: Institut für Virologie und Immunbiologie, Julius-Maximilians-Universität, Würzburg, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Hofmann
authors.affiliation: Institut für Virologie und Immunbiologie, Julius-Maximilians-Universität, Würzburg, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Weißbrich
authors.affiliation: Institut für Virologie und Immunbiologie, Julius-Maximilians-Universität, Würzburg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Spannaus
authors.affiliation: Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany.
authors.forename: Eliana G
authors.initials: EG
authors.lastname: Acosta
authors.affiliation: Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany German Center for Infection Research, Heidelberg University, Heidelberg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Bartenschlager
authors.affiliation: Institut für Physikalische und Theoretische Chemie, Julius-Maximilians-Universität, Würzburg, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Engels
authors.affiliation: Institut für Pharmazie und Biochemie, Johannes Gutenberg-Universität, Mainz, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Schirmeister
authors.affiliation: Institut für Virologie und Immunbiologie, Julius-Maximilians-Universität, Würzburg, Germany Jochen.Bodem@vim.uni-wuerzburg.de.
authors.forename: Jochen
authors.initials: J
authors.lastname: Bodem
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D002460:Cell Line; D003716:Dengue Virus / Q000187:drug effects* / Q000201:enzymology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D062105:Molecular Docking Simulation; D011480:Protease Inhibitors / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D011480:Protease Inhibitors; D012697:Serine Endopeptidases; D017361:Viral Nonstructural Proteins; C504449:NS3 protease, dengue virus; D000085242:Viral Proteases