{"id":16933,"date":"2025-02-26T16:30:42","date_gmt":"2025-02-26T16:30:42","guid":{"rendered":"https:\/\/www.sygnaturediscovery.com\/blog\/phenotypic-screening-for-inflammasome-modulators-a-powerful-example-of-a-high-content-phenotypic-screening-approach-where-there-are-complex-biological-systems\/"},"modified":"2025-02-26T16:30:42","modified_gmt":"2025-02-26T16:30:42","slug":"phenotypic-screening-for-inflammasome-modulators-a-powerful-example-of-a-high-content-phenotypic-screening-approach-where-there-are-complex-biological-systems","status":"publish","type":"blog","link":"https:\/\/www.sygnaturediscovery.com\/fr\/blog\/phenotypic-screening-for-inflammasome-modulators-a-powerful-example-of-a-high-content-phenotypic-screening-approach-where-there-are-complex-biological-systems\/","title":{"rendered":"Phenotypic screening for inflammasome modulators: A powerful example of a high content phenotypic screening approach where there are complex biological systems."},"content":{"rendered":"

Using a phenotypic approach for HTS<\/strong><\/span><\/h2>\n

HTS is a ubiquitous and well-established approach for hit identification; it is often used in conjunction with other techniques, such as virtual and fragment-based drug discovery, for a target-based screening approach. Phenotypic screening, however, is used to identify new molecular target(s) or mechanisms and\/or hits that modulate complex disease mechanisms in a desirable way.<\/span><\/p>\n

The mechanism of a hit target interaction and the target\u2019s identity are initially unknown post-phenotypic screening. This could be because the signalling cascade or disease process is poorly understood. The advantages of using this approach are that it delivers active molecules within a disease relevant cellular background, inclusive of solubility and cell permeability, providing candidates for further medicinal chemistry optimization. Phenotypic screening approaches are often aimed at delivering first-in-class compounds with disease-modifying modalities (Heilker, Lessel and Bischoff, 2019). Usually, developing an appropriate phenotypic assay is a compromise between achieving HTS assay practicality whilst maintaining a strong assay-disease linkage.<\/span><\/p>\n

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NLRP1 mediated inflammasome formation \u2013 a case study\u00a0<\/strong><\/span><\/h2>\n

NLRP1 (aka NALP1) was the first described inflammasome sensor of the Nod-like Receptors (NLR) family, (Taabazuing, Griswold and Bachovchin, 2020). NLRP1 is an innate pattern recognition receptor; it senses molecules that pose a danger to the cell (i.e., bacterial toxins, stress factors and viral proteases). DPP-8\/-9 (a dipeptidyl peptidase) holds NLRP1 in an auto-inhibitory state until stimulation\/release, a process that can be artificially induced by Val-boroPro (VbP), a small-molecular inhibitor of DPP-8\/-9 activity.<\/span><\/p>\n

When active, NLRP1 facilitates inflammasome assembly, enabling activation of caspase-1, which, in turn, leads to the activation and release of IL-1\u00df, IL-18 and Gasdermin (which undergoes oligomerization and forms pores in the membrane), culminating in pyroptic cell death. There is considerable interest in the identification of inhibitors of excessive NLRP1 activity associated with a wide range of chronic inflammatory diseases, like IBD and asthma. Whilst NLRP1 activators are being explored as an immuno-oncology approach to treat cancer.<\/span><\/p>\n

Several pathways can trigger NLRP1 activation that are unique to this class of inflammasome: \u2013<\/span><\/p>\n