Necrosulfonamide

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Necrosulfonamide
Molecular Formula : C18H15N5O6S2
Molecular Weight : 461.47
IUPAC Name (E)-N-[4-[(3-methoxypyrazin-2-yl)sulfamoyl]phenyl]-3-(5-nitrothiophen-2-yl)prop-2-enamide
PubChem Substance ID 468592510 Compound CID: 1566236
CAS Number: 432531-71-0

Necrosulfonamide (NSA) is a potent, selective necroptosis inhibitor with an IC50 value of less than 0.2 µM. It inhibits mixed lineage kinase domain-like protein (MLKL), and blocks necrosis downstream of receptor-interacting serine-threonine kinase 3 (RIP3) activation. Necrosulfonamide has been shown to effectively prevent the MLKL-RIP1-RIP3 necrosome complex from interacting with downstream necrosis effectors.[1][2]

In 2005, necroptosis was described as a novel, proinflammatory cytokine Tumour Necrosis Factor (TNF)-α-triggered, non-apoptotic form of cell death occurring in the absence of caspase-8.[3] TNF-α invariably shows an age-related upregulation[4][5][6], for instance, among the most modulated cytokines, TNF‐α levels increased over 10‐fold in plasma of aged mice compared to young mice.[7] Age-related TNF-α upregulation was associated with frailty, cardiovascular events and rapid cognitive decline in elderly subjects.[8][9]

Necroptosis is mediated by the necrosome, which consists of mixed lineage kinase domain-like protein (MLKL), receptor-interacting protein kinase 1 (RIPK1), and RIPK3.[10]

Later it was shown that NSA can also impact gasdermin D (GSDMD) processing, either directly or upstream via caspase 1, and therefore can inhibit pyroptosis, another form of inflammatory cell death.[11][12][13]

Evidence was presented that the inflammasome sensor, NLRP1, is a key mediator of senescence induced by irradiation both in vitro and in vivo. The NLRP1 inflammasome promotes senescence by regulating the expression of p16, p21, p53, and SASP in Gasdermin D (GSDMD)-dependent manner as these responses are reduced in conditions of NLRP1 insufficiency or GSDMD inhibition. Mechanistically, the NLRP1 inflammasome is activated downstream of the cytosolic DNA sensor cGMP-AMP (cGAMP) synthase (cGAS) in response to genomic damage. These findings provide a rationale for inhibiting the NLRP1 inflammasome-GSDMD axis by using Necrosulfonamide to treat senescence-driven disorders.[14]

References

  1. ↑ Sun, L., Wang, H., Wang, Z., He, S., Chen, S., Liao, D., ... & Wang, X. (2012). Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell, 148(1-2), 213-227. PMID: 22265413 DOI:10.1016/j.cell.2011.11.031
  2. ↑ Liao, D., Sun, L., Liu, W., He, S., Wang, X., & Lei, X. (2014). Necrosulfonamide inhibits necroptosis by selectively targeting the mixed lineage kinase domain-like protein. MedChemComm, 5(3), 333-337.
  3. ↑ Degterev, A., Huang, Z., Boyce, M., Li, Y., Jagtap, P., Mizushima, N., ... & Yuan, J. (2005). Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nature chemical biology, 1(2), 112-119. PMID: 16408008 DOI: 10.1038/nchembio711
  4. ↑ Álvarez-Rodríguez, L., López-Hoyos, M., Muñoz-Cacho, P., & Martínez-Taboada, V. M. (2012). Aging is associated with circulating cytokine dysregulation. Cellular immunology, 273(2), 124-132. PMID: 22316526 DOI: 10.1016/j.cellimm.2012.01.001
  5. ↑ de Gonzalo-Calvo, D., Neitzert, K., Fernández, M., Vega-Naredo, I., Caballero, B., García-Macía, M., ... & Coto-Montes, A. (2010). Differential inflammatory responses in aging and disease: TNF-α and IL-6 as possible biomarkers. Free Radical Biology and Medicine, 49(5), 733-737. PMID: 20639132 DOI: 10.1016/j.freeradbiomed.2010.05.019
  6. ↑ Pinti, M., Gibellini, L., Lo Tartaro, D., De Biasi, S., Nasi, M., Borella, R., ... & Cossarizza, A. (2023). A Comprehensive Analysis of Cytokine Network in Centenarians. International Journal of Molecular Sciences, 24(3), 2719. PMID: 36769039 PMCID: PMC9916918 DOI: 10.3390/ijms24032719
  7. ↑ Liberale, L., Bonetti, N. R., Puspitasari, Y. M., Vukolic, A., Akhmedov, A., Diaz‐Cañestro, C., ... & Camici, G. G. (2021). TNF‐α antagonism rescues the effect of ageing on stroke: Perspectives for targeting inflamm‐ageing. European Journal of Clinical Investigation, 51(11), e13600. PMID: 34076259 PMCID: PMC8596431 DOI: 10.1111/eci.13600
  8. ↑ Michaud, M., Balardy, L., Moulis, G., Gaudin, C., Peyrot, C., Vellas, B., ... & Nourhashemi, F. (2013). Proinflammatory cytokines, aging, and age-related diseases. Journal of the American Medical Directors Association, 14(12), 877-882. PMID: 23792036 DOI: 10.1016/j.jamda.2013.05.009
  9. ↑ Kokkotis, G., Kitsou, K., Xynogalas, I., Spoulou, V., Magiorkinis, G., Trontzas, I., ... & Bamias, G. (2022). Systematic review with meta‐analysis: COVID‐19 outcomes in patients receiving anti‐TNF treatments. Alimentary pharmacology & therapeutics, 55(2), 154-167. PMID: 34881430 DOI: 10.1111/apt.16717
  10. ↑ Ye, K., Chen, Z., & Xu, Y. (2023). The double-edged functions of necroptosis. Cell Death & Disease, 14(2), 163. PMID: 36849530 PMCID: PMC9969390 DOI: 10.1038/s41419-023-05691-6
  11. ↑ Rashidi, M., Simpson, D. S., Hempel, A., Frank, D., Petrie, E., Vince, A., ... & Vince, J. E. (2019). The pyroptotic cell death effector gasdermin D is activated by gout-associated uric acid crystals but is dispensable for cell death and IL-1β release. The Journal of Immunology, 203(3), 736-748. PMID: 31209100 PMCID: PMC6650356 DOI: 10.4049/jimmunol.1900228
  12. ↑ de Vasconcelos, N. M., & Lamkanfi, M. (2020). Recent insights on inflammasomes, gasdermin pores, and pyroptosis. Cold Spring Harbor perspectives in biology, 12(5), a036392. PMID: 31570336 PMCID: PMC7197430 DOI: 10.1101/cshperspect.a036392
  13. ↑ Rathkey, J. K., Zhao, J., Liu, Z., Chen, Y., Yang, J., Kondolf, H. C., ... & Abbott, D. W. (2018). Chemical disruption of the pyroptotic pore-forming protein gasdermin D inhibits inflammatory cell death and sepsis. Science immunology, 3(26), eaat2738.
  14. ↑ Muela-Zarzuela, I., Suarez-Rivero, J. M., Gallardo-Orihuela, A., Wan, C., Izawa, K., de Gregorio-Procopio, M., ... & Cordero, M. D. (2023). NLRP1 inflammasome modulates senescence and senescence-associated secretory phenotype. bioRxiv, 2023-02. PMID: 36798300 PMCID: PMC9934543 DOI: 10.1101/2023.02.06.527254
  15. ↑ Yang, W., Tao, K., Wang, Y., Huang, Y., Duan, C., Wang, T., ... & Li, R. (2022). Necrosulfonamide ameliorates intestinal inflammation via inhibiting GSDMD-medicated pyroptosis and MLKL-mediated necroptosis. Biochemical pharmacology, 206, 115338. PMID: 36347275 DOI: 10.1016/j.bcp.2022.115338
  16. ↑ Ozgen, B., Senol, S. P., Yilmaz, D. E., Temiz-Resitoglu, M., Bahceli, O., & Tunctan, B. (2022). Pyroptosis and Necroptosis Inhibitor Necrosulfonamide Prevents Lipopolysaccharide-Induced Inflammatory Hyperalgesia in Mice https://doi.org/10.21203/rs.3.rs-1727695/v1
  17. ↑ Boersma, B., Möller, K., Wehl, L., Puddinu, V., Huard, A., Fauteux-Daniel, S., ... & Bein, T. (2022). Inhibition of IL-1β release from macrophages targeted with necrosulfonamide-loaded porous nanoparticles. Journal of Controlled Release, 351, 989-1002. PMID: 36202154 DOI: 10.1016/j.jconrel.2022.09.063
  18. ↑ Wu, Y. L., Ou, W. J., Zhong, M., Lin, S., & Zhu, Y. Y. (2022). Gasdermin D Inhibitor Necrosulfonamide Alleviates Lipopolysaccharide/D-galactosamine-induced Acute Liver Failure in Mice. Journal of Clinical and Translational Hepatology, 10(6), 1148-1154. PMID: 36381100 PMCID: PMC9634782 DOI: 10.14218/JCTH.2021.00560
  19. ↑ Ueda, S., Chen-Yoshikawa, T. F., Mineura, K., Yamanashi, K., Oda, H., Yokoyama, Y., ... & Date, H. (2020). Protective Effects of Necrosulfonamide on Ischemia-Reperfusion Injury in Rat Lung. The Journal of Heart and Lung Transplantation, 39(4), S353. https://doi.org/10.1016/j.healun.2020.01.414
  20. ↑ Zhang, X., Zhang, Y., Wang, F., Liu, Y., Yong, V. W., & Xue, M. (2022). Necrosulfonamide alleviates acute brain injury of intracerebral hemorrhage via inhibiting inflammation and necroptosis. Frontiers in Molecular Neuroscience, 15. PMID: 35721316 PMCID: PMC9201046 DOI: 10.3389/fnmol.2022.916249
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