Laboratoire Génomique, Bioinformatique et Applications, EA 4627, Conservatoire National des Arts et Métiers, 2 rue Conté, 75003, Paris, France.
Peptinov SAS, Pépinière Cochin Santé, Hôpital Cochin, 29 rue du Faubourg Saint Jacques, 75014, Paris, France.
Sci Rep. 2017 Jun 13;7(1):3424. doi: 10.1038/s41598-017-03427-z.
TNFα is a homotrimeric pro-inflammatory cytokine, whose direct targeting by protein biotherapies has been an undeniable success for the treatment of chronic inflammatory diseases. Despite many efforts, no orally active drug targeting TNFα has been identified so far. In the present work, we identified through combined in silico/in vitro/in vivo approaches a TNFα direct inhibitor, compound 1, displaying nanomolar and micromolar range bindings to TNFα. Compound 1 inhibits the binding of TNFα with both its receptors TNFRI and TNFRII. Compound 1 inhibits the TNFα induced apoptosis on L929 cells and the TNFα induced NF-κB activation in HEK cells. In vivo, oral administration of compound 1 displays a significant protection in a murine TNFα-dependent hepatic shock model. This work illustrates the ability of low-cost combined in silico/in vitro/in vivo screening approaches to identify orally available small-molecules targeting challenging protein-protein interactions such as homotrimeric TNFα.
TNFα 是一种三聚体促炎细胞因子，其蛋白质生物疗法的直接靶向治疗已成为治疗慢性炎症性疾病的不可否认的成功方法。尽管进行了许多努力，但迄今为止尚未发现针对 TNFα 的口服活性药物。在本工作中，我们通过联合使用计算机模拟/体外/体内方法鉴定出一种 TNFα 直接抑制剂化合物 1，其对 TNFα 的结合具有纳摩尔和微摩尔范围。化合物 1 抑制 TNFα 与其两种受体 TNFRI 和 TNFRII 的结合。化合物 1 抑制 TNFα 在 L929 细胞上诱导的细胞凋亡和 TNFα 在 HEK 细胞中诱导的 NF-κB 激活。在体内，化合物 1 的口服给药在 TNFα 依赖性肝休克小鼠模型中显示出显著的保护作用。这项工作说明了低成本的计算机模拟/体外/体内联合筛选方法能够识别针对挑战性蛋白质-蛋白质相互作用（如三聚体 TNFα）的口服小分子的能力。
