10.1021/acs.jmedchem.5b00612.s001 Lena F. Weigel Lena F. Weigel Christoph Nitsche Christoph Nitsche Dominik Graf Dominik Graf Ralf Bartenschlager Ralf Bartenschlager Christian D. Klein Christian D. Klein Phenylalanine and Phenylglycine Analogues as Arginine Mimetics in Dengue Protease Inhibitors American Chemical Society 2015 Dengue Protease InhibitorsDengue virus peptidic inhibitors nanomolar affinities peptidomimetic drugs serine protease NS 2B phenylglycine derivatives West Nile virus drug discovery Arginine Mimetics dengue virus protease Phenylglycine Analogues phenylalanine side chains 2015-10-08 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/Phenylalanine_and_Phenylglycine_Analogues_as_Arginine_Mimetics_in_Dengue_Protease_Inhibitors/2123887 Dengue virus is an increasingly global pathogen. One of the promising targets for antiviral drug discovery against dengue and related flaviviruses such as West Nile virus is the viral serine protease NS2B-NS3. We here report the synthesis and in vitro characterization of potent peptidic inhibitors of dengue virus protease that incorporate phenylalanine and phenylglycine derivatives as arginine-mimicking groups with modulated basicity. The most promising compounds were (4-amidino)-l-phenylalanine-containing inhibitors, which reached nanomolar affinities against dengue virus protease. The type and position of the substituents on the phenylglycine and phenylalanine side chains has a significant effect on the inhibitory activity against dengue virus protease and selectivity against other proteases. In addition, the non-natural, basic amino acids described here may have relevance for the development of other peptidic and peptidomimetic drugs such as inhibitors of the blood clotting cascade.