OLT1177, a β-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation.
OLT1177, a β-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation.
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DOI：
10.1073/pnas.1716095115
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发表时间：
2018-02-13
影响因子：
11.1
通讯作者：
Dinarello CA
中科院分区：
文献类型：
--
作者：
Marchetti C;Swartzwelter B;Gamboni F;Neff CP;Richter K;Azam T;Carta S;Tengesdal I;Nemkov T;D'Alessandro A;Henry C;Jones GS;Goodrich SA;St Laurent JP;Jones TM;Scribner CL;Barrow RB;Altman RD;Skouras DB;Gattorno M;Grau V;Janciauskiene S;Rubartelli A;Joosten LAB;Dinarello CA
NLRP3炎症体是一种细胞内寡聚体，调节Caspase-1的激活，以处理和分泌IL-1、β和IL-18。虽然有越来越多的证据证明抑制炎症性小体是治疗炎症性疾病的一种选择，但到目前为止，还没有批准的人类制剂。OLT1177是一种β-磺酰基腈分子，被证明对人类是安全的，是一种NLRP3炎症体的选择性抑制剂，具有逆转炎症的代谢成本和治疗IL-1β和IL-18介导的疾病的独特性质。NLRP3炎症体的激活诱导IL-1β和IL-18的成熟，这两种细胞都是治疗急性和慢性炎症性疾病的有效靶点。在这里，我们证明了OLT1177，一种口服活性的β-磺酰基腈分子，抑制了NLRP3炎症体的激活。在体外，纳米分子浓度的OLT1177减少了典型和非典型NLRP3炎性小体激活后IL-1β和IL-18的释放。该分子对NLRC4和AIM2炎性小体没有影响，提示NLRP3具有特异性。在脂多糖刺激的人血巨噬细胞中，当体外浓度低于人体安全血浆浓度100倍时，OLT1177将IL-1β水平降低60%，将IL-18水平降低70%。OLT1177还降低了新鲜获得的人血中性粒细胞中IL-1β的释放和caspase-1的活性。在低温比林相关周期综合征(CAPS)患者分离的单核细胞中，OLT1177分别抑制内毒素诱导的IL-1β释放84%和36%。免疫沉淀和FRET分析表明，OLT1177阻止了NLRP3-ASC以及NLRP3-caspase-1的相互作用，从而抑制了NLRP3炎性小体的齐聚。在无细胞实验中，OLT1177降低了重组NLRP3的ATPase活性，表明NLRP3是直接靶向的。从机制上讲，OLT1177不影响钾外流、基因表达或IL-1β前体的合成。经OLT1177处理的小鼠脾细胞中磷酸化的NF-κB和IKBK的稳态水平显著降低。我们观察到组织匀浆中IL-1β含量降低，氧化应激受限，肌肉氧化代谢增强。健康人每天服用1,000毫克OLT1177，连续服用8天，既没有不良反应，也没有生化或血液学变化。
The NLRP3 inflammasome is an intracellular oligomer regulating the activation of caspase-1 for the processing and secretion of IL-1β and IL-18. Although there is growing evidence to substantiate inflammasome inhibition as a therapeutic option for the treatment of inflammatory diseases, to date, there are no approved humans agents. OLT1177, a β-sulfonyl nitrile molecule, shown to be safe in humans, is a selective inhibitor of the NLRP3 inflammasome, with unique properties to reverse the metabolic costs of inflammation and to treat IL-1β– and IL-18–mediated diseases. Activation of the NLRP3 inflammasome induces maturation of IL-1β and IL-18, both validated targets for treating acute and chronic inflammatory diseases. Here, we demonstrate that OLT1177, an orally active β-sulfonyl nitrile molecule, inhibits activation of the NLRP3 inflammasome. In vitro, nanomolar concentrations of OLT1177 reduced IL-1β and IL-18 release following canonical and noncanonical NLRP3 inflammasome activation. The molecule showed no effect on the NLRC4 and AIM2 inflammasomes, suggesting specificity for NLRP3. In LPS-stimulated human blood-derived macrophages, OLT1177 decreased IL-1β levels by 60% and IL-18 by 70% at concentrations 100-fold lower in vitro than plasma concentrations safely reached in humans. OLT1177 also reduced IL-1β release and caspase-1 activity in freshly obtained human blood neutrophils. In monocytes isolated from patients with cryopyrin-associated periodic syndrome (CAPS), OLT1177 inhibited LPS-induced IL-1β release by 84% and 36%. Immunoprecipitation and FRET analysis demonstrated that OLT1177 prevented NLRP3-ASC, as well as NLRP3-caspase-1 interaction, thus inhibiting NLRP3 inflammasome oligomerization. In a cell-free assay, OLT1177 reduced ATPase activity of recombinant NLRP3, suggesting direct targeting of NLRP3. Mechanistically, OLT1177 did not affect potassium efflux, gene expression, or synthesis of the IL-1β precursor. Steady-state levels of phosphorylated NF-κB and IkB kinase were significantly lowered in spleen cells from OLT1177-treated mice. We observed reduced IL-1β content in tissue homogenates, limited oxidative stress, and increased muscle oxidative metabolism in OLT1177-treated mice challenged with LPS. Healthy humans receiving 1,000 mg of OLT1177 daily for 8 d exhibited neither adverse effects nor biochemical or hematological changes.
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影响因子：
2.8
作者：
Manukyan, Gayane;Petrek, Martin;Boyajyan, Anna
通讯作者：
Boyajyan, Anna
影响因子：
158.5
作者：
Lachmann, Helen J.;Kone-Paut, Isabelle;Hawkins, Philip N.
通讯作者：
Hawkins, Philip N.
DOI：
10.1073/pnas.0611496104
发表时间：
2007-05-08
影响因子：
11.1
作者：
Duncan, Joseph A.;Bergstralht, Daniel T.;Ting, Jenny Pan-Yun
通讯作者：
Ting, Jenny Pan-Yun
影响因子：
4.1
作者：
Infantino, Vittoria;Convertini, Paolo;Iacobazzi, Vito
通讯作者：
Iacobazzi, Vito
影响因子：
5.4
作者：
Cook, Graham P.;Savic, Sinisa;McDermott, Michael F.
通讯作者：
McDermott, Michael F.