C-Terminal residue optimization and fragment merging

• Verfasst von: Behnam, Mira A. M. [VerfasserIn]
• Verfasst von: Nitsche, Christoph [VerfasserIn]
• Verfasst von: Vechi, Sergio [VerfasserIn]
• Verfasst von: Klein, Christian D. [VerfasserIn]
• Titel: C-Terminal residue optimization and fragment merging
• Titelzusatz: discovery of a potent peptide-hybrid inhibitor of Dengue protease
• Verf.angabe: Mira A. M. Behnam, Christoph Nitsche, Sérgio M. Vechi, Christian D. Klein
• E-Jahr: 2014
• Jahr: July 18, 2014
• Umfang: 6 S.
• Illustrationen: Illustrationen
• Fussnoten: Gesehen am 04.09.2020
• Titel Quelle: Enthalten in: ACS medicinal chemistry letters
• Ort Quelle: Washington, DC : ACS, 2010
• Jahr Quelle: 2014
• Band/Heft Quelle: 5(2014), 9, Seite 1037-1042
• ISSN Quelle: 1948-5875
• DOI: doi:10.1021/ml500245v
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1728904528

Abstract

Dengue virus protease is a promising target for the development of antiviral drugs. We describe here a two-step rational optimization that led to the discovery of the potent inhibitor 35 with nanomolar binding affinity at dengue protease serotype 2 (IC50 = 0.6 μM, Ki = 0.4 μM). First, a large number of natural and non-natural amino acids were screened at the C-terminal position of the previously reported, canonical peptide sequence (Cap-Arg-Lys-Nle-NH2). Compared to the reference compound 1 (Bz-Arg-Lys-Nle-NH2, IC50 = 13.3 μM), a 4-fold higher inhibitory potential was observed with the incorporation of a C-terminal phenylglycine (compound 9, IC50 = 3.3 μM). Second, we applied fragment merging of 9 with the previously reported thiazolidinedione peptide hybrid 33 (IC50 = 2.5 μM). This approach led to the fusion of two inhibitor-fragments with micromolar affinity into a 20-fold more potent, competitive inhibitor of dengue protease.