Volltext-Downloads (blau) und Frontdoor-Views (grau)

Highly potent inhibitors of cathepsin K with a differently positioned cyanohydrazide warhead: structural analysis of binding mode to mature and zymogen-like enzymes

  • Cathepsin K (CatK) is a target for the treatment of osteoporosis, arthritis, and bone metastasis. Peptidomimetics with a cyanohydrazide warhead represent a new class of highly potent CatK inhibitors; however, their binding mechanism is unknown. We investigated two model cyanohydrazide inhibitors with differently positioned warheads: an azadipeptide nitrile Gü1303 and a 3-cyano-3-aza-β-amino acid Gü2602. Crystal structures of their covalent complexes were determined with mature CatK as well as a zymogen-like activation intermediate of CatK. Binding mode analysis, together with quantum chemical calculations, revealed that the extraordinary picomolar potency of Gü2602 is entropically favoured by its conformational flexibility at the nonprimed-primed subsites boundary. Furthermore, we demonstrated by live cell imaging that cyanohydrazides effectively target mature CatK in osteosarcoma cells. Cyanohydrazides also suppressed the maturation of CatK by inhibiting the autoactivation of the CatK zymogen. Our results provide structural insights for the rational design of cyanohydrazide inhibitors of CatK as potential drugs.

Export metadata

Additional Services

Search Google Scholar Check availability


Show usage statistics
Document Type:Research Data
Author:Jakub Benýšek, Michal Buša, Petra Rubešová, Jindřich Fanfrlík, Martin Lepšík, Jiří Brynda, Zuzana Matoušková, Ulrike Bartz, Martin Horn, Michael Gütschow, Michael Mareš
Publisher:Taylor & Francis
Date of first publication:2022/02/11
Funding:This work was supported by the project ChemBioDrug CZ.02.1.01/0.0/0.0/16_019/0000729 from ERDF/OPRDE and the institutional project RVO 61388963.
Keyword:Cathepsin K; azadipeptide nitrile; cyanohydrazide warhead; protease inhibitor; structure
Departments, institutes and facilities:Fachbereich Angewandte Naturwissenschaften
Dewey Decimal Classification (DDC):5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften
Entry in this database:2022/04/19
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International