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Peptide–Boronic Acid Inhibitors of Flaviviral Proteases: Medicinal Chemistry and Structural Biology
journal contribution
posted on 2016-11-28, 00:00 authored by Christoph Nitsche, Linlin Zhang, Lena F. Weigel, Jonas Schilz, Dominik Graf, Ralf Bartenschlager, Rolf Hilgenfeld, Christian D. KleinA thousand-fold affinity gain is
achieved by introduction of a
C-terminal boronic acid moiety into dipeptidic inhibitors of the Zika,
West Nile, and dengue virus proteases. The resulting compounds have Ki values in the two-digit nanomolar range, are
not cytotoxic, and inhibit virus replication. Structure–activity
relationships and a high resolution X-ray cocrystal structure with
West Nile virus protease provide a basis for the design of optimized
covalent-reversible inhibitors aimed at emerging flaviviral pathogens.
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K i valuesflaviviral pathogensC-terminal boronic acid moietyWest Nilevirus replicationWest Nile virus proteaseStructural BiologyFlaviviral Proteasesresolution X-ray cocrystal structuredengue virus proteasesaffinity gainMedicinal Chemistrydipeptidic inhibitorsnanomolar rangeoptimized covalent-reversible inhibitors
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