Thiazolidinone–Peptide Hybrids as Dengue Virus Protease Inhibitors with Antiviral Activity in Cell Culture

• Published in: Journal of medicinal chemistry 2013-11, Vol.56 (21), p.8389-8403
• Main Authors: Nitsche, Christoph, Schreier, Verena N, Behnam, Mira A. M, Kumar, Anil, Bartenschlager, Ralf, Klein, Christian D
• Format: Article
• Language: English
• Subjects: Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Cell Culture Techniques; Dengue Virus - drug effects; Dengue Virus - enzymology; Dengue Virus - genetics; Dose-Response Relationship, Drug; Humans; Models, Molecular; Molecular Structure; Peptides - chemistry; Peptides - pharmacology; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Serine Endopeptidases - metabolism; Structure-Activity Relationship; Thiazolidines - chemistry; Thiazolidines - pharmacology; Tumor Cells, Cultured; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - metabolism; Virus Replication - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm400828u

The protease of dengue virus is a promising target for antiviral drug discovery. We here report a new generation of peptide–hybrid inhibitors of dengue protease that incorporate N-substituted 5-arylidenethiazolidinone heterocycles (rhodanines and thiazolidinediones) as N-terminal capping groups of the peptide moiety. The compounds were extensively characterized with respect to inhibition of various proteases, inhibition mechanisms, membrane permeability, antiviral activity, and cytotoxicity in cell culture. A sulfur/oxygen exchange in position 2 of the capping heterocycle (thiazolidinedione-capped vs rhodanine-capped peptide hybrids) has a significant effect on these properties and activities. The most promising in vitro affinities were observed for thiazolidinedione-based peptide hybrids containing hydrophobic groups with K i values between 1.5 and 1.8 μM and competitive inhibition mechanisms. Rhodanine-capped peptide hybrids with hydrophobic substituents have, in correlation with their membrane permeability, a more pronounced antiviral activity in cell culture than the thiazolidinediones.