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

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journal contribution
posted on 14.11.2013 by Christoph Nitsche, Verena N. Schreier, Mira A. M. Behnam, Anil Kumar, Ralf Bartenschlager, Christian D. Klein
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 Ki 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.