AI Article Synopsis
- Necroptosis is a type of programmed cell death linked to several diseases, and researchers are studying new compounds that can inhibit this process.
- A new compound developed is a stronger version of a prior one and effectively prevents necroptosis in both human and mouse cells at very low doses.
- Target engagement studies reveal that this compound interacts with key necroptotic proteins (MLKL, RIPK1, and RIPK3) differently and also has positive effects in a mouse model of systemic inflammatory response syndrome (SIRS).
Article Abstract
Necroptosis is an inflammatory form of programmed cell death that has been implicated in various human diseases. Compound is a more potent analogue of the published compound and inhibits necroptosis in human and murine cells at nanomolar concentrations. Several target engagement strategies were employed, including cellular thermal shift assays (CETSA) and diazirine-mediated photoaffinity labeling via a bifunctional photoaffinity probe derived from compound . These target engagement studies demonstrate that compound binds to all three necroptotic effector proteins (mixed lineage kinase domain-like protein (MLKL), receptor-interacting serine/threonine protein kinase 1 (RIPK1) and receptor-interacting serine/threonine protein kinase 3 (RIPK3)) at different levels and in cells. Compound also shows efficacy in a murine model of systemic inflammatory response syndrome (SIRS).
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| http://dx.doi.org/10.1021/acschembio.0c00482 | DOI Listing |
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