title: Synthesis and biological evaluation of α-ketoamides as inhibitors of the Dengue virus protease with antiviral activity in cell-culture.
abstract: The development of small molecule inhibitors of the viral protease is of considerable interest for the treatment of emergent flaviviral diseases such as Dengue or West Nile fever. Until today little progress has been made in finding drug-like compounds that inhibit the protease and provide a starting point for lead optimization. We describe here the initial steps of a drug discovery effort that focused on the styryl pharmacophore, combined with a ketoamide function to serve as electrophilic trap for the catalytic serine. This resulted in a fragment-like lead compound with reasonable target affinity and good ligand efficiency, which was extensively modified to explore structure-activity relationships. Selected compounds were cross-tested against the West Nile virus protease and thrombin, indicating that selectivity for one or more flaviviral proteases can be achieved. Finally, the antiviral activity of several protease inhibitors was confirmed in a cell-culture model of Dengue virus replication. The SAR presented here may serve as starting point for further drug discovery efforts with the aim of targeting flaviviral proteases.
authors.affiliation: Medizinische Chemie, Universität Heidelberg, Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Steuer
authors.forename: Christian
authors.initials: C
authors.lastname: Gege
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Fischl
authors.forename: Karl H
authors.initials: KH
authors.lastname: Heinonen
authors.forename: Ralf
authors.initials: R
authors.lastname: Bartenschlager
authors.forename: Christian D
authors.initials: CD
authors.lastname: Klein
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D003198:Computer Simulation; D003716:Dengue Virus / Q000201:enzymology*; D006801:Humans; D010447:Peptide Hydrolases / Q000737:chemistry* / Q000378:metabolism; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000737:chemistry* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D014902:West Nile virus / Q000201:enzymology
chemical_list: D000577:Amides; D000998:Antiviral Agents; D011480:Protease Inhibitors; D014764:Viral Proteins; D010447:Peptide Hydrolases