20299-36-9Relevant academic research and scientific papers
Peptide-Boronic Acid Inhibitors of Flaviviral Proteases: Medicinal Chemistry and Structural Biology
Nitsche, Christoph,Zhang, Linlin,Weigel, Lena F.,Schilz, Jonas,Graf, Dominik,Bartenschlager, Ralf,Hilgenfeld, Rolf,Klein, Christian D.
supporting information, p. 511 - 516 (2017/04/27)
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 Ki values in the two-digit nanomolar range
Phenylalanine and Phenylglycine Analogues as Arginine Mimetics in Dengue Protease Inhibitors
Weigel, Lena F.,Nitsche, Christoph,Graf, Dominik,Bartenschlager, Ralf,Klein, Christian D.
supporting information, p. 7719 - 7733 (2015/10/20)
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.
Development of new cyclic plasmin inhibitors with excellent potency and selectivity
Saupe, Sebastian M.,Leubner, Stephanie,Betz, Michael,Klebe, Gerhard,Steinmetzer, Torsten
supporting information, p. 820 - 831 (2013/03/28)
The trypsin-like serine protease plasmin is a target for the development of antifibrinolytic drugs for use in cardiac surgery with cardiopulmonary bypass or organ transplantations to reduce excessive blood loss. The optimization of our recently described substrate-analogue plasmin inhibitors, which were cyclized between their P3 and P2 side chains, provided a new series with improved efficacy and excellent selectivity. The most potent inhibitor 8 binds to plasmin with an inhibition constant of 0.2 nM, whereas Ki values >1 μM were determined for nearly all other tested trypsin-like serine proteases, with the exception of trypsin, which is also inhibited in the nanomolar range. Docking studies revealed a potential binding mode in the widely open active site of plasmin that explains the strong potency and selectivity profile of these inhibitors. The dialkylated piperazine-linker segment contributes to an excellent solubility of all analogues. Based on their overall profile the presented inhibitors are well suited for further development as injectable antifibrinolytic drugs.
