Discovery of potent and selective inhibitors of human NLRP3 with a novel mechanism of action
| Title: | Discovery of potent and selective inhibitors of human NLRP3 with a novel mechanism of action |
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| Authors: | Wilhelmsen, Kevin; Deshpande, Aditi; Tronnes, Sarah; Mahanta, Maitriyee; Banicki, Matthew; Cochran, Mary; Cowdin, Samantha; Fortney, Kristen; Hartman, George; Hughes, Robert E; Montgomery, Rusty; Portillo, Claudia P; Rubin, Paul; Salazar, Taiz; Wang, Yan; Yan, Shijun; Morgan, Barry A; Duisembekova, Assem; Riou, Romane; Marleaux, Michael; Hochheiser, Inga V; Buthmann, Hannes; Ferber, Dominic; Torp, Jane; Wang, Wei; Cranston, Melanie; McKee, Chloe M.; Mawhinney, Thea J.; McKay, Emma C; Eroglu, Fehime K; Kümmerle-Deschner, Jasmin; Weber, Alexander N R; Py, Bénédicte F; Geyer, Matthias; Coll, Rebecca C. |
| Source: | Wilhelmsen, K, Deshpande, A, Tronnes, S, Mahanta, M, Banicki, M, Cochran, M, Cowdin, S, Fortney, K, Hartman, G, Hughes, R E, Montgomery, R, Portillo, C P, Rubin, P, Salazar, T, Wang, Y, Yan, S, Morgan, B A, Duisembekova, A, Riou, R, Marleaux, M, Hochheiser, I V, Buthmann, H, Ferber, D, Torp, J, Wang, W, Cranston, M, McKee, C M, Mawhinney, T J, McKay, E C, Eroglu, F K, Kümmerle-Deschner, J, Weber, A N R, Py, B F, Geyer, M & Coll, R C 2025, 'Discovery of potent and selective inhibitors of human NLRP3 with a novel mechanism of action', .... |
| Publication Year: | 2025 |
| Collection: | Queen's University Belfast: Research Portal |
| Subject Terms: | NLR family; pyrin domain-containing 3 protein/antagonists & inhibitors; humans; animals; mice; inflammasomes/metabolism; HEK293 Cells; peritonitis/drug therapy; drug discovery; signal transduction/drug effects; mutation; interleukin-1beta/metabolism; /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being; name=SDG 3 - Good Health and Well-being |
| Description: | The NLRP3 inflammasome is an intracellular protein complex that causes inflammation via the release of IL-1β and pyroptosis. NLRP3 activation is associated with many age-related inflammatory diseases, and NLRP3 inhibition is a promising therapeutic strategy. We previously performed a DNA-encoded library screen to identify novel NLRP3-binding molecules. Herein we describe the characterization of BAL-0028 as a potent and specific inhibitor of NLRP3 signaling. Notably, BAL-0028 is a poor inhibitor of mouse NLRP3 but inhibits human and primate NLRP3 with nanomolar potency. Using cellular and biochemical analyses, we demonstrate that BAL-0028 binds to the NLRP3 NACHT domain at a site that is distinct from the MCC950-binding pocket. Using humanized NLRP3 mice, we show that a derivative of BAL-0028, BAL-0598, inhibits NLRP3 activation in vivo in a peritonitis model. Finally, we demonstrate that both BAL-0028 and BAL-0598 inhibit select hyperactive NLRP3 mutations associated with autoinflammatory diseases more potently than MCC950. BAL-0028 and BAL-0598 thus represent a new modality for NLRP3 inhibition in inflammatory diseases. |
| Document Type: | article in journal/newspaper |
| File Description: | application/pdf |
| Language: | English |
| ISSN: | 0022-1007; 1540-9538 |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/40892070; info:eu-repo/semantics/altIdentifier/pissn/0022-1007; info:eu-repo/semantics/altIdentifier/eissn/1540-9538 |
| DOI: | 10.1084/jem.20242403 |
| Availability: | https://pure.qub.ac.uk/en/publications/c6b357f8-36c1-4b33-9e72-36a8577362e5; https://doi.org/10.1084/jem.20242403; https://pureadmin.qub.ac.uk/ws/files/653370963/Discovery_of_potent_and_selective_inhibitors_of_human.pdf |
| Rights: | info:eu-repo/semantics/openAccess ; http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: | edsbas.11D57AB7 |
| Database: | BASE |