2. Academic Validation
  3. Design, Synthesis, and Characterization of Dichlorobiphenyl-Derived Inhibitors of the Proprotein Convertase Furin

Design, Synthesis, and Characterization of Dichlorobiphenyl-Derived Inhibitors of the Proprotein Convertase Furin

  • J Med Chem. 2025 Dec 11;68(23):25157-25170. doi: 10.1021/acs.jmedchem.5c02157.
Roman W Lange 1,  Charlotte Boller 1,  Michael Loresch 1,  Konstantin Bloch 2,  Eva Böttcher-Friebertshäuser 2,  Hans Brandstetter 3 4,  Sven O Dahms 3 4,  Torsten Steinmetzer 1
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical Chemistry, Philipps University, Marbacher Weg 10, D-35032 Marburg, Germany.
  • 2 Institute of Virology, Philipps University, Hans-Meerwein-Str. 2, 35043 Marburg, Germany.
  • 3 Department of Biosciences and Medical Biology, Structural Biology Lab, Paris Lodron University, Hellbrunner Straße 34, A-5020 Salzburg, Austria.
  • 4 Center for Tumor Biology and Immunology (CTBI), University of Salzburg, Hellbrunner Straße 34, A-5020 Salzburg, Austria.
PMID: 41319212 DOI: 10.1021/acs.jmedchem.5c02157
Abstract

The proprotein convertase (PC) Furin emerged as promising drug target for the treatment of numerous infectious diseases, Cancer and cystic fibrosis. A recently described nonpeptidic lead structure served as template to develop a new series of PC inhibitors containing a dichlorobiphenyl-derived core segment decorated with a left and right inhibitor arm. The compounds were tested for their inhibitory potency against Furin and the structurally related PC7. The most potent compounds inhibited Furin with Ki values <5 nM, whereas most of them were significantly weaker inhibitors of PC7. Only for one compound, a significant potency with a Ki value of 7.3 nM against PC7 was found. Furthermore, crystal structures of six inhibitors in complex with Furin were determined. Selected inhibitors were additionally tested for their Antiviral potency against the furin-dependent H7N7 influenza A strain SC35M; a significant Antiviral potency was found for compound 9.

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