Gao Jing, Geng Zhiyuan, Yang Hui, Wei Yan, Chen Zhuoxi, Jiang Qian, Chen Yutong, Bi Yi, Zhang Leiming
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, PR China.
School of Traditional Chinese Medicine, Binzhou Medical University, Yantai 264003, PR China.
Bioorg Med Chem Lett. 2025 Dec 1;128:130322. doi: 10.1016/j.bmcl.2025.130322. Epub 2025 Jul 1.
Inflammation plays a crucial role in the onset and progression of sepsis, affecting the overall trajectory of the condition. Additionally, sepsis can result in acute liver injury, which in turn may cause damage to multiple organ systems. Fusidic acid (FA) is a natural product with a steroidal structure and has good anti-inflammatory activity without the hormonal side effects of steroidal anti-inflammatory drugs, so it has potential applications in the development of anti-inflammatory drugs. In the present study, a series of novel FA derivatives were designed and synthesized by structural modification of FA C-3, C-16 and C-21, among which, compound 12 exhibited the strongest anti-inflammatory activity. Compound 12 inhibited nitric oxide (NO) release with an IC of 3.26 ± 0.12 μM. Assessments conducted in both in vivo and in vitro settings indicated that compound 12 can reduce the levels of inflammatory factors, inhibit the activation of inflammatory pathways and improve liver pathological damage. Cellular thermal shift assay showed that compound 12 had binding ability with receptor interaction protein kinase 1 (RIPK1). Furthermore, through the western blotting experiment, this study found that compound 12 inhibited proteins such as RIPK1, p-IκB, p-p65, p-p38, p-JNK and p-ERK within the RIPK1/nuclear factor-κB (NF-κB)/mitogen-activated protein kinases (MAPK) signaling pathway. Concurrently, ELISA experiments indicated that compound 12 could dose-dependently reduce the levels of IL-6 and TNF-α. These results imply that compound 12 can protect the liver from inflammatory invasion by suppressing RIPK1 expression, which subsequently results in decreased activation of the NF-κB and MAPK signaling pathways. In this study, we creatively modified the structure of fusidic acid and obtained a new type of fusidic acid derivative 12. Compared with the glucocorticoids currently used for glucocorticoid receptors, compound 12 is novel in terms of structure and mechanism of action in alleviating sepsis. Our research indicates that compound 12 represents a promising candidate for the design and development of anti-sepsis therapeutics.
炎症在脓毒症的发生和发展中起关键作用，影响病情的整体发展轨迹。此外，脓毒症可导致急性肝损伤，进而可能对多个器官系统造成损害。夫西地酸（FA）是一种具有甾体结构的天然产物，具有良好的抗炎活性，且无甾体抗炎药的激素副作用，因此在抗炎药物开发中具有潜在应用价值。在本研究中，通过对FA的C-3、C-16和C-21进行结构修饰，设计并合成了一系列新型FA衍生物，其中化合物12表现出最强的抗炎活性。化合物12抑制一氧化氮（NO）释放的IC50为3.26±0.12μM。体内和体外实验评估表明，化合物12可降低炎症因子水平，抑制炎症信号通路的激活，并改善肝脏病理损伤。细胞热位移分析表明，化合物12与受体相互作用蛋白激酶1（RIPK1）具有结合能力。此外，通过蛋白质印迹实验，本研究发现化合物12可抑制RIPK1/核因子-κB（NF-κB）/丝裂原活化蛋白激酶（MAPK）信号通路中的RIPK1、p-IκB、p-p65、p-p38、p-JNK和p-ERK等蛋白。同时，酶联免疫吸附测定实验表明，化合物12可剂量依赖性地降低白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）水平。这些结果表明，化合物12可通过抑制RIPK1表达来保护肝脏免受炎症侵袭，进而导致NF-κB和MAPK信号通路的激活减少。在本研究中，我们创新性地修饰了夫西地酸的结构，获得了一种新型夫西地酸衍生物12。与目前用于糖皮质激素受体的糖皮质激素相比，化合物12在结构和减轻脓毒症的作用机制方面具有新颖性。我们的研究表明，化合物12是抗脓毒症治疗药物设计和开发的一个有前景的候选物。
