Phenylalanine and phenylglycine analogues as arginine mimetics in dengue protease inhibitors

• Verfasst von: Weigel, Lena [VerfasserIn]
• Verfasst von: Nitsche, Christoph [VerfasserIn]
• Verfasst von: Graf, Dominik Korbinian [VerfasserIn]
• Verfasst von: Bartenschlager, Ralf [VerfasserIn]
• Verfasst von: Klein, Christian D. [VerfasserIn]
• Titel: Phenylalanine and phenylglycine analogues as arginine mimetics in dengue protease inhibitors
• Verf.angabe: Lena F. Weigel, Christoph Nitsche, Dominik Graf, Ralf Bartenschlager, and Christian D. Klein
• E-Jahr: 2015
• Jahr: September 14, 2015
• Umfang: 15 S.
• Fussnoten: Gesehen am 29.06.2020
• Titel Quelle: Enthalten in: Journal of medicinal chemistry
• Ort Quelle: Washington, DC : ACS, 1959
• Jahr Quelle: 2015
• Band/Heft Quelle: 58(2015), 19, Seite 7719-7733
• ISSN Quelle: 1520-4804
• DOI: doi:10.1021/acs.jmedchem.5b00612
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1702875415

Abstract

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.