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

• Verfasst von: Behnam, Mira A. M. [VerfasserIn]
• Verfasst von: Graf, Dominik Korbinian [VerfasserIn]
• Verfasst von: Bartenschlager, Ralf [VerfasserIn]
• Verfasst von: Zlotos, Darius P. [VerfasserIn]
• Verfasst von: Klein, Christian D. [VerfasserIn]
• Titel: Discovery of nanomolar dengue and West Nile virus protease inhibitors containing a 4-benzyloxyphenylglycine residue
• Verf.angabe: Mira A.M. Behnam, Dominik Graf, Ralf Bartenschlager, Darius P. Zlotos, and Christian D. Klein
• E-Jahr: 2015
• Jahr: November 12, 2015
• Umfang: 17 S.
• Fussnoten: Gesehen am 04.08.2020
• Titel Quelle: Enthalten in: Journal of medicinal chemistry
• Ort Quelle: Washington, DC : ACS, 1959
• Jahr Quelle: 2015
• Band/Heft Quelle: 58(2015), 23, Seite 9354-9370
• ISSN Quelle: 1520-4804
• DOI: doi:10.1021/acs.jmedchem.5b01441
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1726142906

Abstract

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.