title: Peptide-Boronic Acid Inhibitors of Flaviviral Proteases: Medicinal Chemistry and Structural Biology.
abstract: A 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 Kivalues 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.
authors.affiliation: Medicinal Chemistry, IPMB, Heidelberg University , INF-364, 69120 Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Nitsche
authors.affiliation: Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck , Ratzeburger Allee 160, 23562 Lübeck, Germany.|German Center for Infection Research (DZIF) , Sites Hamburg-Lübeck-Borstel-Riems and Heidelberg, Germany.
authors.forename: Linlin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Medicinal Chemistry, IPMB, Heidelberg University , INF-364, 69120 Heidelberg, Germany.
authors.forename: Lena F
authors.initials: LF
authors.lastname: Weigel
authors.affiliation: Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck , Ratzeburger Allee 160, 23562 Lübeck, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Schilz
authors.affiliation: Medicinal Chemistry, IPMB, Heidelberg University , INF-364, 69120 Heidelberg, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Graf
authors.affiliation: German Center for Infection Research (DZIF) , Sites Hamburg-Lübeck-Borstel-Riems and Heidelberg, Germany.|Department of Infectious Diseases, Molecular Virology, Heidelberg University , INF-345, 69120 Heidelberg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Bartenschlager
authors.affiliation: Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck , Ratzeburger Allee 160, 23562 Lübeck, Germany.|German Center for Infection Research (DZIF) , Sites Hamburg-Lübeck-Borstel-Riems and Heidelberg, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Hilgenfeld
authors.affiliation: Medicinal Chemistry, IPMB, Heidelberg University , INF-364, 69120 Heidelberg, Germany.
authors.forename: Christian D
authors.identifier: 0000-0003-3522-9182
authors.initials: CD
authors.lastname: Klein
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000737:chemistry*; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D005416:Flavivirus / Q000187:drug effects* / Q000201:enzymology; D010455:Peptides / Q000737:chemistry*; D011480:Protease Inhibitors / Q000494:pharmacology*; D066244:Proton Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D001897:Boronic Acids; D010455:Peptides; D011480:Protease Inhibitors