Since the discovery of the caspase-2 (Casp2)-mediated ∆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.
Bibliographical noteFunding Information:
We thank Vivien Czipper for excellent technical assistance and Prof. Dr. Sigurd Elz for providing infrastructure. We thank Prof. Dr. Michelle Arkin for Casp2 and Casp3 plasmids and scientific discussion. Steffen Pockes was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, Forschungsstipendium 436921318) and the Fonds der Chemischen Industrie (SK‐208/16). This study used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE‐AC02‐06CH11357. Use of the IMCA‐CAT beamline 17‐ID (or 17‐BM) at the Advanced Photon Source was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with Hauptman‐Woodward Medical Research Institute. This study was supported from NIH grant R01‐AG62199, Caspase‐2 Probe Compounds (awarded to Karen H. Ashe and Michael A. Walters). The authors thank the Lucas Brothers Foundation for financial support. Open Access funding enabled and organized by Projekt DEAL.
© 2022 The Authors. Archiv der Pharmazie published by Wiley-VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.
- Alzheimer's disease
- caspase-2 inhibitors
- protein cleavage
PubMed: MeSH publication types
- Journal Article