Antimicrobial Agents and Chemotherapy p. 1100 - 1109 (2015)
Update date:2022-08-02
Topics:
Wu, Hongmei
Bock, Stefanie
Snitko, Mariya
Berger, Thilo
Weidner, Thomas
Holloway, Steven
Kanitz, Manuel
Diederich, Wibke E.
Steuber, Holger
Walter, Christof
Hofmann, Daniela
Wei?brich, Benedikt
Spannaus, Ralf
Acosta, Eliana G.
Bartenschlager, Ralf
Engels, Bernd
Schirmeister, Tanja
Bodem, Jochen
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.
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