期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 58, 期 23, 页码 9354-9370出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01441
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资金
- German Academic Exchange Service
- Deutsche Forschungsgemeinschaft [KL-1356/3-1]
The dengue virus (DENY) 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 K, 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 mu M at DENV-2 and 15.5 mu M at WNV for the most active analogue.
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