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

Christoph Nitsche; Linlin Zhang; Lena F. Weigel; Jonas Schilz; Dominik Graf; Ralf Bartenschlager; Rolf Hilgenfeld; Christian D. Klein

doi:10.1021/acs.jmedchem.6b01021

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

Christoph Nitsche, Linlin Zhang, Lena F. Weigel, Jonas Schilz, Dominik Graf, Ralf Bartenschlager, Rolf Hilgenfeld, Christian D. Klein^*

^*Korrespondierende/r Autor/-in für diese Arbeit

Institut für Biochemie

130 Zitate (Scopus)

Abstract

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.

Originalsprache	Englisch
Zeitschrift	Journal of Medicinal Chemistry
Jahrgang	60
Ausgabenummer	1
Seiten (von - bis)	511-516
Seitenumfang	6
ISSN	0022-2623
DOIs	https://doi.org/10.1021/acs.jmedchem.6b01021
Publikationsstatus	Veröffentlicht - 12.01.2017

Fördermittel

We thank Dr. Tom Sundermann, Heiko Rudy, Tobias Timmermann, Natascha Stefan, and Yasmin Gu?l for support. Dr. Mascha Ja?kel kindly provided (+)-pinanediol. Dr. Mira A. M. Behnam and Dr. Daizong Lin were valuable partners for discussions. The project was supported by the Deutsche Forschungsgemeinschaft, Grant KL-1356/3-1, and by the German Center for Infection Research (DZIF), Grant 8029801911.

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10.1021/acs.jmedchem.6b01021

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abstract = "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 Ki 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.",

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AU - Graf, Dominik

AU - Bartenschlager, Ralf

AU - Hilgenfeld, Rolf

AU - Klein, Christian D.

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AB - 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 Ki 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.

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

Abstract

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