Thiazolidinone鈥揚eptide Hybrids as Dengue Virus Protease Inhibitors with Antiviral Activity in Cell Culture

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• 作者：Christoph Nitsche ; Verena N. Schreier ; Mira A. M. Behnam ; Anil Kumar ; Ralf Bartenschlager ; Christian D. Klein
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：November 14, 2013
• 年：2013
• 卷：56
• 期：21
• 页码：8389-8403
• 全文大小：830K
• 年卷期：v.56,no.21(November 14, 2013)
• ISSN：1520-4804

文摘

The protease of dengue virus is a promising target for antiviral drug discovery. We here report a new generation of peptide鈥揾ybrid 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 渭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.