Identification of a novel DGKα inhibitor for XLP-1 therapy by virtual screening.
Identification of a novel DGKα inhibitor for XLP-1 therapy by virtual screening.
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通过虚拟筛选鉴定用于 XLP-1 治疗的新型 DGKα 抑制剂。
DOI：
10.1016/j.ejmech.2018.12.061
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发表时间：
2019
影响因子：
6.7
通讯作者：
Baldanzi,Gianluca
中科院分区：
文献类型：
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作者：
Velnati,Suresh;Ruffo,Elisa;Massarotti,Alberto;Talmon,Maria;Varma,KonduruSaiSandeep;Gesu,Alessandro;Fresu,LuigiaGrazia;Snow,AndrewL;Bertoni,Alessandra;Capello,Daniela;Tron,GianCesare;Graziani,Andrea;Baldanzi,Gianluca
作为鉴定可用药的二酰基甘油激酶α (DGKα)抑制剂的一部分，我们使用了基于与两种市售DGKα抑制剂R59022和R59949化学同源性的硅方法。利坦色林和化合物AMB639752从127个化合物中筛选出来，显示出优于两种商业抑制剂的抑制活性，并且对二酰基甘油激酶α亚型具有特异性。有趣的是，AMB639752也缺乏血清素能活性。利坦色林和AMB639752通过抑制完整细胞中的DGKα，恢复SAP缺陷淋巴细胞的再刺激诱导细胞死亡（RICD）的能力也被测试。这两种化合物以低于先前两种可用抑制剂的浓度恢复RICD，表明它们可能用于治疗x连锁淋巴细胞增生性疾病1 (XLP-1)，这是一种罕见的遗传疾病，其中DGKα活性失调。
As part of an effort to identify druggable diacylglycerol kinase alpha (DGKα) inhibitors, we used an in-silico approach based on chemical homology with the two commercially available DGKα inhibitors R59022 and R59949. Ritanserin and compound AMB639752 emerged from the screening of 127 compounds, showing an inhibitory activity superior to the two commercial inhibitors, being furthermore specific for the alpha isoform of diacylglycerol kinase. Interestingly, AMB639752 was also devoid of serotoninergic activity. The ability of both ritanserin and AMB639752, by inhibiting DGKα in intact cells, to restore restimulation induced cell death (RICD) in SAP deficient lymphocytes was also tested. Both compounds restored RICD at concentrations lower than the two previously available inhibitors, indicating their potential use for the treatment of X-linked lymphoproliferative disease 1 (XLP-1), a rare genetic disorder in which DGKα activity is deregulated.