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Discovery of novel elongator protein 2 inhibitors by compound library screening using surface plasmon resonance

机译：使用表面等离振子共振通过化合物文库筛选发现新型延伸蛋白2抑制剂

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摘要

Tumour necrosis factor-α (TNF-α) is a pleiotropic cytokine that becomes elevated in chronic inflammatory states, including slowing down osteogenic differentiation, which leads to bone dysplasia in long-term inflammatory microenvironments. The elongator complex plays a role in gene regulation and association with various cellular activities, including the downstream signal transduction of TNF-α in osteogenic cells. To find an inhibitor of Elongator Protein 2 (Elp2), we performed a compound library screen and verified the pharmaceutical effects of candidate compounds on the mouse myoblast cell (C2C12) and mouse osteoblastic cells (MC3T3-E1). The commercial FDA-approved drug (FD) library and the bioactive compound (BC) library were used as candidate libraries. After a label-free, high-throughput affinity measurement with surface plasmon resonance (SPRi), seven kinds of compounds showed binding affinity with mouse Elp2 protein. The seven candidates were then used to perform an inhibition test with TNF-α-induced C2C12 and MC3T3-E1 cell lines. One candidate compound reduced the differentiation suppression caused by TNF-α with resuscitated alkaline phosphatase (ALP) activity, mineralization intensity and expression of osteogenic differentiation marker genes. The results of our study provide a competitive candidate to mitigate the TNF-α-induced osteogenic differentia.
机译：肿瘤坏死因子-α（TNF-α）是一种多效性细胞因子，在慢性炎症状态下会升高，包括减慢成骨细胞分化，从而导致长期炎症微环境下的骨发育异常。延伸复合物在基因调节和与各种细胞活动相关的作用中起作用，包括成骨细胞中TNF-α的下游信号转导。为了找到Elongator Protein 2（Elp2）的抑制剂，我们进行了化合物库筛选，并验证了候选化合物对小鼠成肌细胞（C2C12）和小鼠成骨细胞（MC3T3-E1）的药理作用。商业FDA批准的药物（FD）库和生物活性化合物（BC）库用作候选库。在使用表面等离振子共振（SPRi）进行无标记，高通量亲和力测量后，七种化合物显示出与小鼠Elp2蛋白的结合亲和力。然后使用这七个候选物对TNF-α诱导的C2C12和MC3T3-E1细胞系进行抑制试验。一种候选化合物通过复苏的碱性磷酸酶（ALP）活性，矿化强度和成骨分化标记基因的表达降低了TNF-α引起的分化抑制。我们的研究结果为减轻TNF-α诱导的成骨性差异提供了一个有竞争力的候选人。

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