N-sulfonyl peptide-hybrids as a new class of dengue virus protease inhibitors

• Verfasst von: Behrouz, Somayeh [VerfasserIn]
• Verfasst von: Kühl, Nikos [VerfasserIn]
• Verfasst von: Klein, Christian D. [VerfasserIn]
• Titel: N-sulfonyl peptide-hybrids as a new class of dengue virus protease inhibitors
• Verf.angabe: Somayeh Behrouz, Nikos Kühl, Christian D. Klein
• E-Jahr: 2023
• Jahr: 7 March 2023
• Umfang: 14 S.
• Fussnoten: Online verfügbar 1. März 2023, Artikelversion 7. März 2023 ; Gesehen am 24.05.2023
• Titel Quelle: Enthalten in: European journal of medicinal chemistry
• Ort Quelle: Amsterdam [u.a.] : Elsevier Science, 1987
• Jahr Quelle: 2023
• Band/Heft Quelle: 251(2023) vom: März, Artikel-ID 115227, Seite 1-14
• ISSN Quelle: 1768-3254
• DOI: doi:10.1016/j.ejmech.2023.115227
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: -Sulfonyl peptide-hybrids
• Sach-SW: Dengue
• Sach-SW: Flavivirus
• Sach-SW: NS2B-NS3 protease
• Sach-SW: Sulfonamide
• K10plus-PPN: 1846117720

Abstract

Dengue virus (DENV) from the Flaviviridae family causes an epidemic disease that seriously threatens human life. The viral serine protease NS2B-NS3 is a promising target for drug development against DENV and other flaviviruses. We here report the design, synthesis, and in-vitro characterization of potent peptidic inhibitors of DENV protease with a sulfonyl moiety as N-terminal cap, thereby creating sulfonamide-peptide hybrids. The in-vitro target affinities of some synthesized compounds were in the nanomolar range, with the most promising derivative reaching a Ki value of 78 nM against DENV-2 protease. The synthesized compounds did not have relevant off-target activity nor cytotoxicity. The metabolic stability of compounds against rat liver microsomes and pancreatic enzymes was remarkable. In general, the integration of sulfonamide moieties at the N-terminus of peptidic inhibitors proved to be a promising and attractive strategy for further drug development against DENV infections.