Bresinsky, Merlin and Strasser, Jessica M. and Hubmann, Alexander and Vallaster, Bernadette and McCue, William M. and Fuller, Jessica and Singh, Gurpreet and Nelson, Kathryn M. and Cuellar, Matthew E. and Finzel, Barry C. and Ashe, Karen H. and Walters, Michael A. and Pockes, Steffen (2022) Characterization of caspase-2 inhibitors based on specific sites of caspase-2-mediated proteolysis. ARCHIV DER PHARMAZIE, 355 (9): e2200095. ISSN 0365-6233, 1521-4184
Full text not available from this repository. (Request a copy)Abstract
Since the discovery of the caspase-2 (Casp2)-mediated increment tau314 cleavage product and its associated impact on tauopathies such as Alzheimer's disease, the design of selective Casp2 inhibitors has become a focus in medicinal chemistry research. In the search for new lead structures with respect to Casp2 selectivity and drug-likeness, we have taken an approach by looking more closely at the specific sites of Casp2-mediated proteolysis. Using seven selected protein cleavage sequences, we synthesized a peptide series of 53 novel molecules and studied them using in vitro pharmacology, molecular modeling, and crystallography. Regarding Casp2 selectivity, AcITV(Dab)D-CHO (23) and AcITV(Dap)D-CHO (26) demonstrated the best selectivity (1-6-fold), although these trends were only moderate. However, some analogous tetrapeptides, most notably AcDKVD-CHO (45), showed significantly increased Casp3 selectivities (>100-fold). Tetra- and tripeptides display decreased or no Casp2 affinity, supporting the assumption that a motif of five amino acids is required for efficient Casp2 inhibition. Overall, the results provide a reasonable basis for the development of both selective Casp2 and Casp3 inhibitors.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | COVALENT DOCKING; DRUG DISCOVERY; LIBRARIES; CLEAVAGE; FAMILY; POTENT; Alzheimer's disease; caspase-2; caspase-2 inhibitors; protein cleavage; tauopathies |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 08 Feb 2024 11:56 |
| Last Modified: | 08 Feb 2024 11:56 |
| URI: | https://pred.uni-regensburg.de/id/eprint/57496 |
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