Peptide–Boronic Acid Inhibitors of Flaviviral Proteases: Medicinal Chemistry and Structural Biology

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• 作者：Christoph Nitsche ; Linlin Zhang ; Lena F. Weigel ; Jonas Schilz ; Dominik Graf ; Ralf Bartenschlager ; Rolf Hilgenfeld ; Christian D. Klein
• 刊名：Journal of Medicinal Chemistry
• 出版年：2017
• 出版时间：January 12, 2017
• 年：2017
• 卷：60
• 期：1
• 页码：511-516
• 全文大小：386K
• ISSN：1520-4804

文摘

A thousand-fold affinity gain is achieved by introduction of a C-terminal boronic acid moiety into dipeptidic inhibitors of the Zika, West Nile, and dengue virus proteases. The resulting compounds have K_i values in the two-digit nanomolar range, are not cytotoxic, and inhibit virus replication. Structure–activity relationships and a high resolution X-ray cocrystal structure with West Nile virus protease provide a basis for the design of optimized covalent-reversible inhibitors aimed at emerging flaviviral pathogens.