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

Institute of Biochemistry

121 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
Journal	Journal of Medicinal Chemistry
Volume	60
Issue number	1
Pages (from-to)	511-516
Number of pages	6
ISSN	0022-2623
DOIs	https://doi.org/10.1021/acs.jmedchem.6b01021
Publication status	Published - 12.01.2017

Funding

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.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1021/acs.jmedchem.6b01021

Cite this

@article{01500a2f638448488a6aa7cc57d10ad8,

title = "Peptide-Boronic Acid Inhibitors of Flaviviral Proteases: Medicinal Chemistry and Structural Biology",

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.\}",

year = "2017",

month = jan,

day = "12",

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

language = "English",

volume = "60",

pages = "511--516",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "Elsevier Masson s.r.l.",

number = "1",

}

TY - JOUR

T1 - Peptide-Boronic Acid Inhibitors of Flaviviral Proteases: Medicinal Chemistry and Structural Biology

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

M3 - Journal articles

C2 - 27966962

AN - SCOPUS:85018193437

SN - 0022-2623

VL - 60

SP - 511

EP - 516

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

Abstract

Funding

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this