Discovery of Nanomolar Dengue and West Nile Virus Protease Inhibitors Containing a 4-Benzyloxyphenylglycine Residue

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• 作者：Mira A. M. Behnam ; Dominik Graf ; Ralf Bartenschlager ; Darius P. Zlotos ; Christian D. Klein
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：December 10, 2015
• 年：2015
• 卷：58
• 期：23
• 页码：9354-9370
• 全文大小：833K
• ISSN：1520-4804

文摘

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 K_i 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 渭M at DENV-2 and 15.5 渭M at WNV for the most active analogue.