| Autor: |
Nitsche C; Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology IPMB, Heidelberg University , Im Neuenheimer Feld 364, 69120 Heidelberg, Germany., Schreier VN, Behnam MA, Kumar A, Bartenschlager R, Klein CD |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2013 Nov 14; Vol. 56 (21), pp. 8389-403. Date of Electronic Publication: 2013 Oct 22. |
| DOI: |
10.1021/jm400828u |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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