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  • Title: Novel dengue virus NS2B/NS3 protease inhibitors.
    Author: Wu H, Bock S, Snitko M, Berger T, Weidner T, Holloway S, Kanitz M, Diederich WE, Steuber H, Walter C, Hofmann D, Weißbrich B, Spannaus R, Acosta EG, Bartenschlager R, Engels B, Schirmeister T, Bodem J.
    Journal: Antimicrob Agents Chemother; 2015 Feb; 59(2):1100-9. PubMed ID: 25487800.
    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.
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