Sterol-binding proteins are important regulators of lipid homeostasis and membrane integrity; however, the discovery of selective modulators can be challenging due to structural similarities in the sterol-binding domains. We report the discovery of potent and selective inhibitors of oxysterol-binding protein (OSBP), which we term oxybipins. Sterol-containing chemical chimeras aimed at identifying new sterol-binding proteins by targeted degradation, led to a significant reduction in levels of Golgi-associated proteins. The degradation occurred in lysosomes, concomitant with changes in protein glycosylation, indicating that the degradation of Golgi proteins was a downstream effect. By establishing a sterol transport protein biophysical assay panel, we discovered that the oxybipins potently inhibited OSBP, resulting in blockage of retrograde trafficking and attenuating Shiga toxin toxicity. As the oxybipins do not target other sterol transporters and only stabilized OSBP in intact cells, we advocate their use as tools to study OSBP function and therapeutic relevance.

甾醇结合蛋白是脂质稳态和膜完整性的重要调节剂；然而，由于甾醇结合域的结构相似性，选择性调节剂的发现可能具有挑战性。我们报告发现了有效且选择性的氧甾醇结合蛋白（OSBP）抑制剂，我们将其称为奥比平（oxybipins）。含有甾醇的化学嵌合体旨在通过靶向降解来识别新的甾醇结合蛋白，导致高尔基体相关蛋白水平显着降低。降解发生在溶酶体中，伴随着蛋白质糖基化的变化，表明高尔基体蛋白的降解是下游效应。通过建立甾醇转运蛋白生物物理检测组，我们发现奥比平能有效抑制 OSBP，从而阻断逆行运输并减弱志贺毒素毒性。由于奥比平不靶向其他甾醇转运蛋白，仅稳定完整细胞中的 OSBP，因此我们主张将其用作研究 OSBP 功能和治疗相关性的工具。