Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
Department of Diabetes Complications & Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
Molecules. 2023 Jul 11;28(14):5332. doi: 10.3390/molecules28145332.
The regulation of bile acid pathways has become a particularly promising therapeutic strategy for a variety of metabolic disorders, cancers, and diseases. However, the hydrophobicity of bile acids has been an obstacle to clinical efficacy due to off-target effects from rapid drug absorption. In this report, we explored a novel strategy to design new structure fragments based on lithocholic acid (LCA) with improved hydrophilicity by introducing a polar "oxygen atom" into the side chain of LCA, then (i) either retaining the carboxylic acid group or replacing the carboxylic acid group with (ii) a diol group or (iii) a vinyl group. These novel fragments were evaluated using luciferase-based reporter assays and the MTS assay. Compared to LCA, the result revealed that the two lead compounds - were well tolerated in vitro, maintaining similar potency and efficacy to LCA. The MTS assay results indicated that cell viability was not affected by dose dependence (under 25 µM). Additionally, computational model analysis demonstrated that compounds - formed more extensive hydrogen bond networks with Takeda G protein-coupled receptor 5 (TGR5) than LCA. This strategy displayed a potential approach to explore the development of novel endogenous bile acids fragments. Further evaluation on the biological activities of the two lead compounds is ongoing.
胆汁酸途径的调控已成为治疗各种代谢紊乱、癌症和疾病的一种极具前景的治疗策略。然而，由于胆汁酸的疏水性，药物吸收迅速导致药物产生脱靶效应，从而限制了其临床疗效。在本报告中，我们探索了一种新的策略，通过在胆酸（LCA）的侧链中引入极性“氧原子”，设计了基于 LCA 的具有改善亲水性的新型结构片段，然后（i）保留羧酸基团，或（ii）用二醇基团或（iii）乙烯基基团取代羧酸基团。这些新型片段通过基于荧光素酶的报告基因检测和 MTS 检测进行评估。与 LCA 相比，结果表明两种先导化合物-在体外具有良好的耐受性，保持与 LCA 相似的效力和功效。MTS 检测结果表明，细胞活力不受剂量依赖性影响（低于 25µM）。此外，计算模型分析表明，化合物-与 Takeda G 蛋白偶联受体 5（TGR5）形成了比 LCA 更广泛的氢键网络。该策略为探索新型内源性胆汁酸片段的开发提供了一种潜在的方法。正在对这两种先导化合物的生物学活性进行进一步评估。
