Thiazolidinone-peptide hybrids as dengue virus protease inhibitors with antiviral activity in cell culture

Christoph Nitsche, Verena N. Schreier, Mira A.M. Behnam, Anil Kumar, Ralf Bartenschlager, Christian D. Klein*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

130 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)8389-8403
Number of pages15
JournalJournal of Medicinal Chemistry
Volume56
Issue number21
DOIs
Publication statusPublished - 14 Nov 2013
Externally publishedYes

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