Backbone modifications in peptidic inhibitors of flaviviral proteases

• Verfasst von: Jakob, Alexander [VerfasserIn]
• Verfasst von: Sundermann, Tom R. [VerfasserIn]
• Verfasst von: Klein, Christian D. [VerfasserIn]
• Titel: Backbone modifications in peptidic inhibitors of flaviviral proteases
• Verf.angabe: Alexander K.M.H. Jakob, Tom R. Sundermann, Christian D. Klein
• E-Jahr: 2019
• Jahr: August 2019
• Umfang: 5 S.
• Fussnoten: Gesehen am 10.07.2019
• Titel Quelle: Enthalten in: Bioorganic & medicinal chemistry letters
• Ort Quelle: Amsterdam [u.a.] : Elsevier Science, 1991
• Jahr Quelle: 2019
• Band/Heft Quelle: 29(2019), 15, Seite 1913-1917
• ISSN Quelle: 1464-3405
• DOI: doi:10.1016/j.bmcl.2019.05.054
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Dengue
• Sach-SW: Flavivirus
• Sach-SW: Peptidomimetics
• Sach-SW: Protease inhibitor
• Sach-SW: West Nile fever
• K10plus-PPN: 1668927195

Abstract

The NS2B-NS3 protease is a promising target for the development of drugs against dengue virus (DENV), West Nile virus (WNV) and related flaviviruses. We report the systematic variation of the peptide backbone of the two lead compounds Bz-Arg-Lys-d-Phg-NH2 and Bz-Arg-Lys-d-Phg(OBn)-NH2. While inhibitory activity against WNV protease was generally decreased, the inhibitory potency against DENV protease could be conserved and increased in several peptidomimetics, particularly in those containing a (NMe)arginine fragment or an N-terminal α-keto amide. Methylation at the α-position of the C-terminal phenylglycine led to a 6-fold higher potency against DENV protease. Peptidomimetics with modified backbone showed increased resistance against hydrolytic attack by trypsin and α-chymotrypsin.