<br>从海洋微生物衍生的天然产物中发现针对 LXRα 的抗高胆固醇血症药物,Journal of Natural Products

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从海洋微生物衍生的天然产物中发现针对 LXRα 的抗高胆固醇血症药物
Journal of Natural Products ( IF 3.3 ) Pub Date : 2024-02-09 , DOI: 10.1021/acs.jnatprod.3c01029
Yuwei Fang _{1,

2} , Jianglian She _{2,

3} , Xi Zhang ₂ , Tanwei Gu ₂ , Danni Xie ₂ , Xiaowei Luo ₁ , Xiangxi Yi ₁ , Chenghai Gao ₁ , Yonghong Liu _{1,

3} , Cuixian Zhang ₄ , Lan Tang ₂ , Xuefeng Zhou ₃

Affiliation

采用计算机分子对接与LXRα和表型分析相结合的策略，在我们小组近年来收集的包含205种海洋微生物衍生天然产物的小型文库中发现了抗高胆固醇血症药物。通过实时 qPCR 和蛋白质印迹 (WB) 分析以及表面等离振子共振 (SPR) 分析，两种 Fumitremorgin 衍生物 12 R ,13 S -二羟基fumitremorgin C ( 1 ) 和胰前列腺素 A ( 3 ) 被鉴定为潜在的 LXRα 激动剂) 测定。利用不同的细胞和小鼠模型深入研究了1和3的抗高胆固醇作用及其机制，其中LXRα的研究至关重要。化合物1或3在肝脂肪变性细胞模型中表现出有效逆转过度脂质积累的能力，并显着降低高胆固醇饮食 (HCD) 喂养的野生型小鼠的肝损伤和血液胆固醇水平，而在HCD 喂养的 LXRα 敲除小鼠。此外， 1和3通过抑制 HCD 喂养的小鼠中甾醇调节元件结合蛋白 1 (SREBP1) 的表达，从而减轻脂毒性，从而优于常见的 LXRα 激动剂。因此，本研究强调了两种海洋微生物衍生的针对 LXRα 的抗高胆固醇血症药物的发现。

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Discovery of Anti-Hypercholesterolemia Agents Targeting LXRα from Marine Microorganism-Derived Natural Products

A strategy integrating in silico molecular docking with LXRα and phenotypic assays was adopted to discover anti-hypercholesterolemia agents in a small library containing 205 marine microorganism-derived natural products, collected by our group in recent years. Two fumitremorgin derivatives, 12R,13S-dihydroxyfumitremorgin C (1) and tryprostatin A (3), were identified as potential LXRα agonists, by real-time qPCR and Western blot (WB) analysis, together with a surface plasmon resonance (SPR) assay. The anti-hypercholesterolemic effects of 1 and 3, together with their mechanisms, were investigated in depth using different cell and mouse models, among which the study of LXRα is of crucial importance. Compound 1 or 3 exhibited the capacity to effectively reverse excessive lipid accumulation in a hepatic steatosis cell model and significantly reduce liver damage and blood cholesterol levels in high cholesterol diet (HCD)-fed wild-type mice, whereas those beneficial effects were completely nullified in HCD-fed LXRα-knockout mice. Furthermore, 1 and 3 outperformed common LXRα agonists by suppressing the expression of sterol regulatory element-binding protein 1 (SREBP1) in HCD-fed mice, mitigating lipotoxicity. Thus, this study highlights the discovery of two marine microorganism-derived anti-hypercholesterolemia agents targeting LXRα.

更新日期：2024-02-09

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