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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 37 (1): 515-526 (2022)
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…
Synthesis of (Di)thiahelicenes and Dithiophenohelicenes by [2+2+2] Cycloisomerization of Alkynes
Helvetica Chimica Acta 2022: Early View
Use of Raman and Raman optical activity to extract atomistic details of saccharides in aqueous solution
PLOS Computational Biology 18 (1): e1009678 (2022)
31P NMR parameters may facilitate the stereochemical analysis of phosphorus-containing compounds
Journal of Magnetic Resonance 336: 107149 (2022)