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

0553871 - ÚOCHB 2023 RIV GB eng J - Článek v odborném periodiku
Benýšek, Jakub - Buša, Michal - Rubešová, Petra - Fanfrlík, Jindřich - Lepšík, Martin - Brynda, Jiří - Matoušková, Zuzana - Bartz, U. - Horn, Martin - Gütschow, M. - Mareš, Michael
Highly potent inhibitors of cathepsin K with a differently positioned cyanohydrazide warhead: structural analysis of binding mode to mature and zymogen-like enzymes.
Journal of Enzyme Inhibition and Medicinal Chemistry. Roč. 37, č. 1 (2022), s. 515-526. ISSN 1475-6366. E-ISSN 1475-6374
Grant CEP: GA MŠMT(CZ) EF16_019/0000729
Institucionální podpora: RVO:61388963
Klíčová slova: Cathepsin K * protease inhibitor * cyanohydrazide warhead * azadipeptide nitrile * crystal structure
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 5.6, rok: 2022
Způsob publikování: Open access
https://doi.org/10.1080/14756366.2021.2024527

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.
Trvalý link: http://hdl.handle.net/11104/0328551


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