Design, synthesis, andin vitroevaluation of aza-peptide aldehydes and ketones as novel and selective protease inhibitors

0537297 - BC 2021 RIV GB eng J - Článek v odborném periodiku
Corrigan, T.S. - Diaz, L.M.L. - Border, S.E. - Ratigan, S.C. - Kasper, K.Q. - Sojka, Daniel - Fajtova, P. - Caffrey, C.R. - Salvesen, G. S. - McElroy, C.A. - Hadad, C.M. - Ekici, O.D.
Design, synthesis, andin vitroevaluation of aza-peptide aldehydes and ketones as novel and selective protease inhibitors.
Journal of Enzyme Inhibition and Medicinal Chemistry. Roč. 35, č. 1 (2020), s. 1387-1402. ISSN 1475-6366. E-ISSN 1475-6374
Grant CEP: GA MŠMT(CZ) EF16_019/0000759
Institucionální podpora: RVO:60077344
Klíčová slova: asparaginyl endopeptidase * schistosoma-mansoni * michael acceptors * caspase family * key mediators * legumain * expression * potent * generation * epoxides * Proteasome inhibitor * caspase and legumain inhibitors * aza-peptide carbonyls * anticancer * antiparasitic
Obor OECD: Microbiology
Impakt faktor: 5.051, rok: 2020
Způsob publikování: Open access
https://www.tandfonline.com/doi/pdf/10.1080/14756366.2020.1781107?needAcces

Aza-peptide aldehydes and ketones are a new class of reversible protease inhibitors that are specific for the proteasome and clan CD cysteine proteases. We designed and synthesised aza-Leu derivatives that were specific for the chymotrypsin-like active site of the proteasome, aza-Asp derivatives that were effective inhibitors of caspases-3 and6, and aza-Asn derivatives that inhibitedS. mansoniandI. ricinuslegumains. The crystal structure of caspase-3 in complex with our caspase-specific aza-peptide methyl ketone inhibitor with an aza-Asp residue at P1 revealed a covalent linkage between the inhibitor carbonyl carbon and the active site cysteinyl sulphur. Aza-peptide aldehydes and ketones showed no cross-reactivity towards cathepsin B or chymotrypsin. The initialin vitroselectivity of these inhibitors makes them suitable candidates for further development into therapeutic agents to potentially treat multiple myeloma, neurodegenerative diseases, and parasitic infections.
Trvalý link: http://hdl.handle.net/11104/0315029