Contact

  • Academic
    marinaf1@stanford.edu
    University - Student Department: School of Medicine Position: Graduate, Medicine

Additional Info

  • Mail Code: 5151

All Publications

  • Chemoproteomics Identifies State-Dependent and Proteoform-Selective Caspase-2 Inhibitors. Journal of the American Chemical Society Castellón, J. O., Ofori, S., Burton, N. R., Julio, A. R., Turmon, A. C., Armenta, E., Sandoval, C., Boatner, L. M., Takayoshi, E. E., Faragalla, M., Taylor, C., Zhou, A. L., Tran, K., Shek, J., Yan, T., Desai, H. S., Fregoso, O. I., Damoiseaux, R., Backus, K. M. 2024; 146 (22): 14972-14988

    Abstract

    Caspases are a highly conserved family of cysteine-aspartyl proteases known for their essential roles in regulating apoptosis, inflammation, cell differentiation, and proliferation. Complementary to genetic approaches, small-molecule probes have emerged as useful tools for modulating caspase activity. However, due to the high sequence and structure homology of all 12 human caspases, achieving selectivity remains a central challenge for caspase-directed small-molecule inhibitor development efforts. Here, using mass spectrometry-based chemoproteomics, we first identify a highly reactive noncatalytic cysteine that is unique to caspase-2. By combining both gel-based activity-based protein profiling (ABPP) and a tobacco etch virus (TEV) protease activation assay, we then identify covalent lead compounds that react preferentially with this cysteine and afford a complete blockade of caspase-2 activity. Inhibitory activity is restricted to the zymogen or precursor form of monomeric caspase-2. Focused analogue synthesis combined with chemoproteomic target engagement analysis in cellular lysates and in cells yielded both pan-caspase-reactive molecules and caspase-2 selective lead compounds together with a structurally matched inactive control. Application of this focused set of tool compounds to stratify the functions of the zymogen and partially processed (p32) forms of caspase-2 provide evidence to support that caspase-2-mediated response to DNA damage is largely driven by the partially processed p32 form of the enzyme. More broadly, our study highlights future opportunities for the development of proteoform-selective caspase inhibitors that target nonconserved and noncatalytic cysteine residues.

    View details for DOI 10.1021/jacs.3c12240

    View details for PubMedID 38787738

  • Closing the gap: Identifying barriers and facilitators to receiving caudal analgesia for pediatric patients from primarily Spanish-speaking families SPA-AAP Pediatric Anesthesiology Faragalla, M. H., et al 2024