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

  • J Med Chem. 2017 Jan 12;60(1):511-516. doi: 10.1021/acs.jmedchem.6b01021.
Christoph Nitsche  1 ,  Linlin Zhang  2  3 ,  Lena F Weigel  1 ,  Jonas Schilz  2 ,  Dominik Graf  1 ,  Ralf Bartenschlager  3  4 ,  Rolf Hilgenfeld  2  3 ,  Christian D Klein  1
Affiliations
  • 1. Medicinal Chemistry, IPMB, Heidelberg University , INF-364, 69120 Heidelberg, Germany.
  • 2. Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck , Ratzeburger Allee 160, 23562 Lübeck, Germany.
  • 3. German Center for Infection Research (DZIF) , Sites Hamburg-Lübeck-Borstel-Riems and Heidelberg, Germany.
  • 4. Department of Infectious Diseases, Molecular Virology, Heidelberg University , INF-345, 69120 Heidelberg, Germany.
PMID: 27966962 DOI: 10.1021/acs.jmedchem.6b01021
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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