Phospholipids are ligands for nuclear hormone receptors (NRs) that regulate transcriptional programs relevant to normal physiology and disease. Here, we demonstrate that mimicking phospholipid-NR interactions is a robust strategy to improve agonists of liver receptor homolog-1 (LRH-1), a therapeutic target for colitis. Conventional LRH-1 modulators only partially occupy the binding pocket, leaving vacant a region important for phospholipid binding and allostery. Therefore, we constructed a set of molecules with elements of natural phospholipids appended to a synthetic LRH-1 agonist. We show that the phospholipid-mimicking groups interact with the targeted residues in crystal structures and improve binding affinity, LRH-1 transcriptional activity, and conformational changes at a key allosteric site. The best phospholipid mimetic markedly improves colonic histopathology and disease-related weight loss in a murine T cell transfer model of colitis. This evidence of in vivo efficacy for an LRH-1 modulator in colitis represents a leap forward in agonist development.

磷脂是核激素受体 (NR) 的配体，调节与正常生理和疾病相关的转录程序。在这里，我们证明模仿磷脂-NR 相互作用是改善肝受体同源物 1 (LRH-1)（结肠炎治疗靶点）激动剂的有效策略。传统的 LRH-1 调节剂仅部分占据结合袋，留下对磷脂结合和变构重要的空区域。因此，我们构建了一组将天然磷脂元素附加到合成 LRH-1 激动剂上的分子。我们表明，磷脂模拟基团与晶体结构中的目标残基相互作用，并提高结合亲和力、LRH-1 转录活性和关键变构位点的构象变化。在小鼠结肠炎 T 细胞转移模型中，最好的磷脂模拟物可显着改善结肠组织病理学和疾病相关的体重减轻。 LRH-1 调节剂在结肠炎中的体内疗效证据代表了激动剂开发的飞跃。