Authors:	Wu, Hongmei Bock, Stefanie Snitko, Mariya Berger, Thilo Weidner, Thomas Holloway, Steven Kanitz, Manuel Diederich, Wibke E. Steuber, Holger Walter, Christof Hofmann, Daniela Weißbrich, Benedikt Spannaus, Ralf Acosta, Eliana G. Bartenschlager, Ralf Engels, Bernd Schirmeister, Tanja Bodem, Jochen
Title:	Novel dengue virus NS2B/NS3 protease inhibitors
Online publication date:	7-Dec-2022
Year of first publication:	2015
Language:	english
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.
DDC:	570 Biowissenschaften 570 Life sciences
Institution:	Johannes Gutenberg-Universität Mainz
Department:	FB 09 Chemie, Pharmazie u. Geowissensch.
Place:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-8490
Version:	Published version
Publication type:	Zeitschriftenaufsatz
License:	In Copyright
Information on rights of use:	http://rightsstatements.org/vocab/InC/1.0/
Journal:	Antimicrobial agents and chemotherapy 59 2
Pages or article number:	1100 1109
Publisher:	Soc.
Publisher place:	Washington, DC
Issue date:	2015
ISSN:	1098-6596 0066-4804
Publisher URL:	http://dx.doi.org/10.1128/AAC.03543-14
Publisher DOI:	10.1128/AAC.03543-14
Appears in collections:	DFG-OA-Publizieren (2012 - 2017)