Necrosulfonamide functions as an inhibitor of necroptosis by selectively inhibiting the mixed lineage kinase domain-like protein (MLKL). It obstructs the interaction between the MLKL-RIP1-RIP3 necrosome complex and its subsequent effectors. During necrosis initiation, MLKL is an essential target of RIP3. Necrosulfonamide acts downstream of RIP3 activation to specifically impede necrosis. It hinders necrosis driven by MLKL by inhibiting the functionality of its N-terminal CC domain[1].
体外研究
Necrosulfonamide (NSA) effectively protects human cells from TNF-a, Smac mimetic (LCL161), z-VAD-fmk-triggered necroptosis, but not mouse cells. The reason for the species specificity of necrosulfonamide is that the cysteine at residue 86 in human MLKL that is covalently modified by necrosulfonamide is replaced by a tryptophan residue in mouse MLKL[1].
NSA blocks phospho-MLKL targeting to membranes and attenuats liposome leakage without preventing MLKL phosphorylation[2].
Necrosulfonamide 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Bel-7402 and SMMC-7721 cells
1 µM
Inhibition of necroptosis
Cell Death Discov. 2021 Apr 16;7(1):83.
primary neuronal cells
5 µM
14 days
NSA markedly reduced PFFs-induced neuronal cell death
Mol Neurodegener. 2023 Dec 1;18(1):94.
B16 melanoma cells
1 μM
24 h
To evaluate the effect of NSA on cell death, results showed that NSA did not inhibit cell death induced by erastin or RSL3
Pharmacol Res. 2023 Oct;196:106899.
RAW264.7 cells
10 μM
4 h
To detect cell death in the necroptosis pathway, results showed that the NSA inhibitor could partially reduce PrsA-induced cell death
Virulence. 2023 Dec;14(1):2249779.
human monocytes
5 µM
3, 6, 12, 24 hpi
Inhibits pMLKL membrane translocation, prevents H7N9-induced monocyte cell death
Cell Death Dis. 2019 Jun 5;10(6):442.
Caco-2 cells
1 µM
1 h
Treatment with necrosulfonamide resulted in a decrease in SpvB-mediated cell death, indicating that SpvB promotes necroptosis through MLKL phosphorylation.
Cell Death Discov. 2022 Feb 2;8(1):44.
primary MEF cells
5 µM
24 h
NSA exhibited neuroprotective effects against 6-OHDA plus TNF-α-induced cell death
Mol Neurodegener. 2023 Dec 1;18(1):94.
mPDAC cells
1 μM
24 h
To evaluate the effect of Necrosulfonamide on ferroptosis, results showed that Necrosulfonamide had no significant effect on ferroptosis
Nat Commun. 2021 Jan 28;12(1):647.
Necrosulfonamide 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Myocardial ischemia-reperfusion injury model
Intraperitoneal injection
20 mg/kg
Once daily for 3 weeks
NSA treatment significantly reduced plasma cTnT, CK-MB, and LDH content in KO mice with I/R injury, suggesting ameliorated cardiac damage.
Redox Biol. 2024 Dec;78:103400
Mice
PANC1 or MIAPaCa2 xenograft models
Intraperitoneal injection
10 mg/kg
Once every other day for 2 weeks
To evaluate the effect of Necrosulfonamide on the anticancer activity induced by ferroptosis, results showed that Necrosulfonamide had no significant effect on ferroptosis
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