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

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 p...

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Main Authors: Behrouz, Somayeh (Author) , Kühl, Nikos (Author) , Klein, Christian D. (Author)
Format: Article (Journal)
Language:English
Published: 7 March 2023
In: European journal of medicinal chemistry
Year: 2023, Volume: 251, Pages: 1-14
ISSN:1768-3254
DOI:10.1016/j.ejmech.2023.115227
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.ejmech.2023.115227
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0223523423001939
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Author Notes:Somayeh Behrouz, Nikos Kühl, Christian D. Klein
Description
Summary: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.
Item Description:Online verfügbar 1. März 2023, Artikelversion 7. März 2023
Gesehen am 24.05.2023
Physical Description:Online Resource
ISSN:1768-3254
DOI:10.1016/j.ejmech.2023.115227

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