Optimization of Substrate-Analogue Furin Inhibitors,ChemMedChem

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Optimization of Substrate-Analogue Furin Inhibitors
ChemMedChem ( IF 3.6 ) Pub Date : 2017-11-16 09:15:42 , DOI: 10.1002/cmdc.201700596
Teodora Ivanova ₁ , Kornelia Hardes ₁ , Stephanie Kallis _{2,

3} , Sven O. Dahms _{4,

5} , Manuel E. Than ₄ , Sebastian Künzel ₆ , Eva Böttcher-Friebertshäuser ₇ , Iris Lindberg ₈ , Guan-Sheng Jiao _{9,

10} , Ralf Bartenschlager _{2,

3} , Torsten Steinmetzer ₁

Affiliation

Institute of Pharmaceutical Chemistry; Philipps University; Marbacher Weg 6 35032 Marburg Germany
Department of Infectious Diseases, Molecular Virology; Heidelberg University; Im Neuenheimer Feld 345 69120 Heidelberg Germany
German Center for Infection Research, Heidelberg Partner Site; Im Neuenheimer Feld 345 69120 Heidelberg Germany
Protein Crystallography Group; Leibniz Institute on Aging-Fritz Lipmann Institute; Beutenbergstr. 11 07745 Jena Germany
Department of Molecular Biology; University of Salzburg; Billrothstrasse 11 5020 Salzburg Austria
Faculty of Engineering Sciences; Hochschule Ansbach; Residenzstraße 8 91522 Ansbach Germany
Institute of Virology; Philipps University; Hans-Meerwein-Str. 2 Marburg Germany
Department of Anatomy and Neurobiology; University of Maryland Medical School; Baltimore MD 21201 USA
Department of Chemistry; Hawaii Biotech, Inc.; Honolulu HI USA
MedChem ShortCut LLC; Pearl City HI USA

Going (anti)viral: Given the limited tolerability of our benzamidine-derived furin inhibitor MI-1148, new analogues with less basic P1 groups were prepared. Some of them inhibit furin in the low nanomolar range, but are less active in cells. Secondly, only the P2 arginine has been replaced by lysine. This inhibitor possesses a similar inhibitory potency and activity in cell culture assays. Moreover, it exhibits decreased toxicity in mice.

中文翻译：

底物-模拟弗林蛋白酶抑制剂的优化

抗病毒：由于我们的苯甲idine衍生的弗林蛋白酶抑制剂MI-1148的耐受性有限，因此制备了具有较少碱性P1基团的新类似物。它们中的一些在低纳摩尔范围内抑制弗林蛋白酶，但在细胞中活性较低。其次，只有P2精氨酸被赖氨酸取代。这种抑制剂在细胞培养试验中具有类似的抑制能力和活性。而且，它在小鼠中表现出降低的毒性。

更新日期：2017-11-16

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