Mechanism and disease implications of necroptosis and neuronal inflammation.
Mechanism and disease implications of necroptosis and neuronal inflammation.
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DOI：
10.1038/s41419-018-0872-7
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发表时间：
2018-09-05
影响因子：
9
通讯作者：
Rodrigues CMP
中科院分区：
文献类型：
--
作者：
Oliveira SR;Amaral JD;Rodrigues CMP
Necroptosis is a form of regulated necrotic cell death, executed via activation of receptor-interacting protein 1 (RIP1) and 3 (RIP3), which is activated under apoptosisdeficient conditions. Although necroptosis could be initiated by several stimuli, the activation mediated by death receptors, particularly tumor necrosis factor receptor 1 (TNFR1), is the most widely studied 1. At the molecular level, this type of cell death includes auto-and trans-phosphorylation of RIP1 and RIP3, which leads to the assembly of an amyloid-like multiprotein complex, socalled necrosome 1. In addition to RIP1 and RIP3, mixed lineage kinase domain-like (MLKL) pseudokinase is also involved in necroptosis, being recruited and phosphorylated at T357/S358 by RIP3. Upon phosphorylation, MLKL oligomerizes and migrates from the cytoplasm to the cell membrane, thus causing necrotic membrane disruption and cell death 2. Growing evidence shows that necroptosis is a key event in the pathogenesis of several diseases with an inflammatory component. Regulated necrosis was first investigated in ischemic brain injury in 2005 3, and later in liver injury 4 but also in neurodegenerative diseases. In fact, necroptosis has been implicated in Huntington’s disease 5, multiple sclerosis 6, Alzheimer’s disease 7 and, more recently, in Parkinson’s disease 8. Of importance is the fact that genetic or chemical blockage of necroptosis results in disease amelioration. Pharmacological inhibition of necroptosis was first investigated using necrostatin-1 (Nec-1), an allosteric inhibitor of RIP1, which stabilizes a specific inactive conformation of the kinase domain 9. However, in vivo studies with this molecule were limited due to its poor pharmacokinetic properties, including a short half-life of approximately 1h, along with reduced solubility. In addition, Nec-1 presented off-target activity, inhibiting indoleamine 2, 3-dioxygenease (IDO), an enzyme involved in adaptive and innate immune responses 9. To overcome these limitations, Nec-1 molecule was further optimized, leading to the development of necrostatin-1 stable (Nec-1s), selective for RIP1-kinase inhibition, but still with poor pharmacokinetic properties 9. Other molecules targeting different components of the necroptotic signaling pathway were also described, including GSK’872 and necrosulfonamide that inhibit RIP3 and MLKL, respectively. Nevertheless, all of them presented several limitations. GSK2982772, a RIP1-kinase inhibitor, is currently in phase 2a clinical studies for psoriasis, rheumatoid arthritis, and ulcerative colitis 10, which highlights the relevance and importance of pharmacological inhibition of necroptosis in the context of disease.In our recent paper published in Cell Death Discovery 11, we screened a small in-house library of molecules for their ability to inhibit necroptosis after successful method development using an in vitro model of microglia necroptosis, based on the murine BV2 microglia cell line (Fig. 1). The phenotypic screening identified a new oxazolone—Oxa12—that strongly inhibits necroptosis in two different cellular models—BV2 and L929 cells—without cytotoxicity associated. Further, Oxa12 inhibited important markers of necroptosis commitment, including necrosome assembly and MLKL S358 phosphorylation in BV2 cells. Of note, in silico molecular docking calculations for Oxa12 inside the RIP1 kinase domain revealed, that without any constraint, Oxa12 is occupying a region similar to the co-crystallized inhibitor. Oxa12, however, is slightly rotated in the binding pocket when compared with the crystallographic ligand, being close to Asp156, Leu157, Met67, and Met95, which may enable important hydrogen bonds and …
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影响因子：
7
作者：
Oliveira SR;Dionísio PA;Brito H;Franco L;Rodrigues CAB;Guedes RC;Afonso CAM;Amaral JD;Rodrigues CMP
通讯作者：
Rodrigues CMP
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影响因子：
12.4
作者：
Huang Z;Zhou T;Sun X;Zheng Y;Cheng B;Li M;Liu X;He C
通讯作者：
He C
影响因子：
7.3
作者：
Harris, Philip A.;Berger, Scott B.;Bertin, John
通讯作者：
Bertin, John
影响因子：
64.5
作者：
Li J;McQuade T;Siemer AB;Napetschnig J;Moriwaki K;Hsiao YS;Damko E;Moquin D;Walz T;McDermott A;Chan FK;Wu H
通讯作者：
Wu H
影响因子：
25
作者：
Caccamo, Antonella;Branca, Caterina;Oddo, Salvatore
通讯作者：
Oddo, Salvatore