Small Molecule Inhibitors of Lymphocyte Perforin as Focused Immunosuppressants for Infection and Autoimmunity

Spicer, JA; Huttunen, KM; Jose, J; Dimitrov, I; Akhlaghi, H; Sutton, VR; Voskoboinik, I; Trapani, J

Author(s): Spicer, JA; Huttunen, KM; Jose, J; Dimitrov, I; Akhlaghi, H; Sutton, VR; Voskoboinik, I; Trapani, J;
Details: Publication Year 2022-11-10,Volume 65,Issue #21,Page 14305-14325
Journal Title: Journal of Medicinal Chemistry
Publication Type: Review
Abstract: New drugs that precisely target the immune mechanisms critical for cytotoxic T lymphocyte (CTL) and natural killer (NK) cell driven pathologies are desperately needed. In this perspective, we explore the cytolytic protein perforin as a target for therapeutic intervention. Perforin plays an indispensable role in CTL/NK killing and controls a range of immune pathologies, while being encoded by a single copy gene with no redundancy of function. An immunosuppressant targeting this protein would provide the first-ever therapy focused specifically on one of the principal cell death pathways contributing to allotransplant rejection and underpinning multiple autoimmune and postinfectious diseases. No drugs that selectively block perforin-dependent cell death are currently in clinical use, so this perspective will review published novel small molecule inhibitors, concluding with in vivo proof-of-concept experiments performed in mouse models of perforin-mediated immune pathologies that provide a potential pathway toward a clinically useful therapeutic agent.
Keywords: Mice; Animals; Perforin; *Cytotoxicity, Immunologic; *Autoimmunity; Immunosuppressive Agents/pharmacology/therapeutic use/metabolism; Pore Forming Cytotoxic Proteins; Membrane Glycoproteins/metabolism; T-Lymphocytes, Cytotoxic
Department(s): Laboratory Research
PubMed ID: 36263926
Publisher's Version: https://doi.org/10.1021/acs.jmedchem.2c01338
Open Access at Publisher's Site: https://doi.org/10.1021/acs.jmedchem.2c01338
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-04-11 03:02:40

Last Modified: 2025-04-11 03:05:16