Bresinsky M, Strasser JM, Hubmann A, Vallaster B, McCue WM, Fuller J, Singh G, Nelson KM, Cuellar ME, Finzel BC, Ashe KH, Walters MA, Pockes S. Characterization of Caspase-2 Inhibitors Based on Specific Sites of Caspase-2-Mediated Proteolysis. Archiv der Pharmazie. 2022;355(9):e2200095. PMID: 35642311. DOI: 10.1002/ardp.202200095.
Summary
This study advanced caspase-2 inhibitor discovery by designing peptides based on naturally occurring caspase-2 cleavage sequences. The authors synthesized 53 molecules and evaluated their potency, selectivity, and binding characteristics using pharmacological, molecular modeling, and crystallographic methods. Although caspase-2 selectivity remained moderate for some analogs, the work revealed key sequence requirements for caspase-2 recognition and showed that five-residue motifs are important for efficient inhibition.
Key Findings
- Fifty-three peptide analogs were synthesized and tested.
- Natural caspase-2 cleavage sites informed inhibitor design.
- Five-residue motifs appeared important for caspase-2 affinity.
- Some analogs showed strong caspase-3 selectivity, clarifying selectivity determinants.
Impact on the Caspase-2/Tau Program
This paper refined structure-activity relationships for caspase-2 inhibitor development. It helped define the sequence and binding-site features needed to improve potency and selectivity.