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Discovery of nanomolar dengue and West Nile virus protease inhibitors containing a 4-benzyloxyphenylglycine residue

The dengue virus (DENV) and West Nile Virus (WNV) NS2B-NS3 proteases are attractive targets for the development of dual-acting therapeutics against these arboviral pathogens. We present the synthesis and extensive biological evaluation of inhibitors that contain benzyl ethers of 4-hydroxyphenylglyci...

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Bibliographic Details
Main Authors: Behnam, Mira A. M. (Author) , Graf, Dominik Korbinian (Author) , Bartenschlager, Ralf (Author) , Zlotos, Darius P. (Author) , Klein, Christian D. (Author)
Format: Article (Journal)
Language:English
Published: November 12, 2015
In: Journal of medicinal chemistry
Year: 2015, Volume: 58, Issue: 23, Pages: 9354-9370
ISSN:1520-4804
DOI:10.1021/acs.jmedchem.5b01441
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1021/acs.jmedchem.5b01441
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Author Notes:Mira A.M. Behnam, Dominik Graf, Ralf Bartenschlager, Darius P. Zlotos, and Christian D. Klein
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Summary:The dengue virus (DENV) and West Nile Virus (WNV) NS2B-NS3 proteases are attractive targets for the development of dual-acting therapeutics against these arboviral pathogens. We present the synthesis and extensive biological evaluation of inhibitors that contain benzyl ethers of 4-hydroxyphenylglycine as non-natural peptidic building blocks synthesized via a copper-complex intermediate. A three-step optimization strategy, beginning with fragment growth of the C-terminal 4-hydroxyphenylglycine to the benzyloxy ether, followed by C- and N-terminal optimization, and finally fragment merging generated compounds with in vitro affinities in the low nanomolar range. The most promising derivative reached Ki values of 12 nM at the DENV-2 and 39 nM at the WNV proteases. Several of the newly discovered protease inhibitors yielded a significant reduction of dengue and West Nile virus titers in cell-based assays of virus replication, with an EC50 value of 3.4 μM at DENV-2 and 15.5 μM at WNV for the most active analogue.
Item Description:Gesehen am 04.08.2020
Physical Description:Online Resource
ISSN:1520-4804
DOI:10.1021/acs.jmedchem.5b01441

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