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Proline-Based Allosteric Inhibitors of Zika and Dengue Virus NS2B/NS3 Proteases
journal contribution
posted on 2019-12-13, 13:38 authored by Benedikt Millies, Franziska von Hammerstein, Andrea Gellert, Stefan Hammerschmidt, Fabian Barthels, Ulrike Göppel, Melissa Immerheiser, Fabian Elgner, Nathalie Jung, Michael Basic, Christian Kersten, Werner Kiefer, Jochen Bodem, Eberhard Hildt, Maike Windbergs, Ute A. Hellmich, Tanja SchirmeisterThe NS2B/NS3 serine proteases of the Zika and Dengue
flaviviruses
are attractive targets for the development of antiviral drugs. We
report the synthesis and evaluation of a new, proline-based compound
class that displays allosteric inhibition of both proteases. The structural
features relevant for protease binding and inhibition were determined
to establish them as new lead compounds for flaviviral inhibitors.
Based on our structure–activity relationship studies, the molecules
were further optimized, leading to inhibitors with submicromolar IC50 values and improved lipophilic ligand efficiency. The allosteric
binding site in the proteases was probed using mutagenesis and covalent
modification of the obtained cysteine mutants with maleimides, followed
by computational elucidation of the possible binding modes. In infected
cells, antiviral activity against Dengue virus serotype 2 using prodrugs
of the inhibitors was observed. In summary, a novel inhibitor scaffold
targeting an allosteric site shared between flaviviral NS2B/NS3 proteases
is presented whose efficacy is demonstrated in vitro and in cellulo.
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Keywords
protease bindingNS 2B serine proteasesDengue Virus NS 2B Proteasesflaviviral inhibitorslipophilic ligand efficiencycovalent modificationDengue virus serotype 2binding modesdisplays allosteric inhibitioncysteine mutantsallosteric sitenovel inhibitor scaffoldsubmicromolar IC 50 valuesflaviviral NS 2B proteasesproline-based compound classZikaallosteric binding siteProline-Based Allosteric InhibitorsDengue flaviviruses
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