Journal article
Small Molecule Inhibitors of Lymphocyte Perforin as Focused Immunosuppressants for Infection and Autoimmunity
JA Spicer, KM Huttunen, J Jose, I Dimitrov, H Akhlaghi, VR Sutton, I Voskoboinik, J Trapani
Journal of Medicinal Chemistry | Published : 2022
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. N..
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Funding Acknowledgements
A significant proportion of the drug development work described in this review was funded through the generosity of the Wellcome Trust (U.K.), through the strategic drug discovery initiative (SDDI) scheme (2011-17). J.T. is funded by past and continuing grants from the National Health and Medical Research Council (NHMRC) Australia, and through the generous philanthropy of Mrs. Rosie Lew and the Peter MacCallum Cancer Foundation. J.A.S. acknowledges funding from the Cancer Research Trust New Zealand, Leukaemia and Blood Cancer New Zealand, the Auckland Medical Research Foundation, and the Maurice Wilkins Centre for Research Excellence and is extremely grateful for fellowship support from Cancer Society Auckland Northland, a division of the Cancer Society of New Zealand. The table of contents graphic was created using BioRender.com. The authors would also like to extend their sincere gratitude to Dr. David Middlemiss for his invaluable contributions to much of the work described above.