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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

130 Citations (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.

Original language	English
Pages (from-to)	511-516
Number of pages	6
Journal	Journal of Medicinal Chemistry
Volume	60
Issue number	1
DOIs	https://doi.org/10.1021/acs.jmedchem.6b01021
Publication status	Published - 12 Jan 2017
Externally published	Yes

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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.",

author = "Christoph Nitsche and Linlin Zhang and Weigel, \{Lena F.\} and Jonas Schilz and Dominik Graf and Ralf Bartenschlager and Rolf Hilgenfeld and Klein, \{Christian D.\}",

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doi = "10.1021/acs.jmedchem.6b01021",

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AU - Nitsche, Christoph

AU - Zhang, Linlin

AU - Weigel, Lena F.

AU - Schilz, Jonas

AU - Graf, Dominik

AU - Bartenschlager, Ralf

AU - Hilgenfeld, Rolf

AU - Klein, Christian D.

PY - 2017/1/12

Y1 - 2017/1/12

N2 - 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.

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.

UR - https://www.scopus.com/pages/publications/85018193437

U2 - 10.1021/acs.jmedchem.6b01021

DO - 10.1021/acs.jmedchem.6b01021

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JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 1

ER -

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

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