Bresinsky M, Strasser JM, Vallaster B, Liu P, McCue WM, Fuller J, Hubmann A, Singh G, Nelson KM, Cuellar ME, Wilmot CM, Finzel BC, Ashe KH, Walters MA, Pockes S. Structure-Based Design and Biological Evaluation of Novel Caspase-2 Inhibitors Based on the Peptide AcVDVAD-CHO and the Caspase-2-Mediated Tau Cleavage Sequence YKPVD314. ACS Pharmacology & Translational Science. 2022;5(1):20-40. PMID: 35059567. DOI: 10.1021/acsptsci.1c00251.
Summary
This medicinal chemistry study mapped the caspase-2 binding site using pentapeptide inhibitors inspired by AcVDVAD-CHO and the tau cleavage sequence surrounding Asp314. The authors synthesized and tested 35 inhibitors, evaluated caspase-2 potency and caspase-3 selectivity, and used computational modeling and crystallography to interpret binding interactions. The study identified nanomolar inhibitors with improved selectivity and provided early structure-activity relationships for caspase-2 inhibitor design.
Key Findings
- Pentapeptide inhibitors achieved nanomolar caspase-2 potency.
- Selectivity over caspase-3 was improved for selected analogs.
- Modeling and crystallography informed binding hypotheses.
- The tau cleavage sequence guided inhibitor design.
Impact on the Caspase-2/Tau Program
This paper established the first detailed medicinal chemistry framework for selective caspase-2 inhibition. It provided lead structures and design principles for more drug-like inhibitors.