Thiazolidinoneâ€“Peptide Hybrids as Dengue Virus Protease Inhibitors with Antiviral Activity in Cell Culture
Christoph Nitsche , Verena Schreier , Mira A.M. Behnam , Anil Kumar , Ralf Bartenschlager , and Christian D.P. Klein
J. Med. Chem., Just Accepted Manuscript
Publication Date (Web): October 1, 2013
Copyright © 2013 American Chemical Society
The protease of dengue virus is a promising target for antiviral drug discovery. We here report a new generation of peptideâ€“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 M 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.