Genuine selective caspase-2 inhibition with new irreversible small peptidomimetics

Caspase-2 (Casp2) is a promising therapeutic target in several human diseases, including nonalcoholic steatohepatitis (NASH) and Alzheimer’s disease (AD). However, the design of an active-site-directed inhibitor selective to individual caspase family members is challenging because caspases have extr...

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Published in:	Cell death & disease Vol. 13; no. 11; p. 959
Main Authors:	Bosc, Elodie, Anastasie, Julie, Soualmia, Feryel, Coric, Pascale, Kim, Ju Youn, Wang, Lily Q., Lacin, Gullen, Zhao, Kaitao, Patel, Ronak, Duplus, Eric, Tixador, Philippe, Sproul, Andrew A., Brugg, Bernard, Reboud-Ravaux, Michelle, Troy, Carol M., Shelanski, Michael L., Bouaziz, Serge, Karin, Michael, El Amri, Chahrazade, Jacotot, Etienne D.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 15-11-2022 Springer Nature B.V Nature Publishing Group
Subjects:	13/2 13/31 13/62 42/109 631/45/607/468 631/80/82/23 692/308/153 82/29 96/100 96/95 Alzheimer's disease Antibodies Biochemistry Biomedical and Life Sciences Caspase 2 - metabolism Caspase 3 - metabolism Caspase-2 Cell Biology Cell Culture Cell death Cell lines Cellular stress response Chemical Sciences Enzyme kinetics Hippocampus Humans Hydroxamic acid Immunology Isomers Life Sciences Medicinal Chemistry Neurodegenerative diseases Neurons - metabolism Non-alcoholic Fatty Liver Disease - drug therapy Non-alcoholic Fatty Liver Disease - metabolism Peptidomimetics Peptidomimetics - metabolism Peptidomimetics - pharmacology Pharmaceutical sciences Pharmacology Sterol regulatory element-binding protein Therapeutic targets β-Amyloid steatohepatitis Alzheimer’s Disease cell death drug design peptidomimetics irreversible inhibitors synapse loss Caspase-2
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Summary:	Caspase-2 (Casp2) is a promising therapeutic target in several human diseases, including nonalcoholic steatohepatitis (NASH) and Alzheimer’s disease (AD). However, the design of an active-site-directed inhibitor selective to individual caspase family members is challenging because caspases have extremely similar active sites. Here we present new peptidomimetics derived from the VDVAD pentapeptide structure, harboring non-natural modifications at the P2 position and an irreversible warhead. Enzyme kinetics show that these new compounds, such as LJ2 or its specific isomers LJ2a, and LJ3a, strongly and irreversibly inhibit Casp2 with genuine selectivity. In agreement with the established role of Casp2 in cellular stress responses, LJ2 inhibits cell death induced by microtubule destabilization or hydroxamic acid-based deacetylase inhibition. The most potent peptidomimetic, LJ2a, inhibits human Casp2 with a remarkably high inactivation rate ( k 3 / K i ~5,500,000 M −1 s − 1 ), and the most selective inhibitor, LJ3a, has close to a 1000 times higher inactivation rate on Casp2 as compared to Casp3. Structural analysis of LJ3a shows that the spatial configuration of C α at the P2 position determines inhibitor efficacy. In transfected human cell lines overexpressing site-1 protease (S1P), sterol regulatory element-binding protein 2 (SREBP2) and Casp2, LJ2a and LJ3a fully inhibit Casp2-mediated S1P cleavage and thus SREBP2 activation, suggesting a potential to prevent NASH development. Furthermore, in primary hippocampal neurons treated with β-amyloid oligomers, submicromolar concentrations of LJ2a and of LJ3a prevent synapse loss, indicating a potential for further investigations in AD treatment.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 PMCID: PMC9666555
ISSN:	2041-4889 2041-4889
DOI:	10.1038/s41419-022-05396-2