Whitmarsh-Everiss Thomas, Olsen Asger Hegelund, Laraia Luca
Department of Chemistry, Technical University of Denmark, Kemitorvet 207, 2800, Kongens Lyngby, Denmark.
Angew Chem Int Ed Engl. 2021 Dec 13;60(51):26755-26761. doi: 10.1002/anie.202111639. Epub 2021 Nov 16.
Cholesterol transport proteins regulate a vast array of cellular processes including lipid metabolism, vesicular and non-vesicular trafficking, organelle contact sites, and autophagy. Despite their undoubted importance, the identification of selective modulators of this class of proteins has been challenging due to the structural similarities in the cholesterol-binding site. Herein we report a general strategy for the identification of selective inhibitors of cholesterol transport proteins via the synthesis of a diverse sterol-inspired compound collection. Fusion of a primary sterol fragment to an array of secondary privileged scaffolds led to the identification of potent and selective inhibitors of the cholesterol transport protein Aster-C, which displayed a surprising preference for the unnatural-sterol AB-ring stereochemistry and new inhibitors of Aster-A. We propose that this strategy can and should be applied to any therapeutically relevant sterol-binding protein.
胆固醇转运蛋白调节着大量细胞过程，包括脂质代谢、囊泡和非囊泡运输、细胞器接触位点以及自噬。尽管它们具有毋庸置疑的重要性，但由于胆固醇结合位点的结构相似性，鉴定这类蛋白的选择性调节剂一直具有挑战性。在此，我们报告一种通过合成多种受甾醇启发的化合物库来鉴定胆固醇转运蛋白选择性抑制剂的通用策略。将一个初级甾醇片段与一系列二级优势骨架融合，从而鉴定出了胆固醇转运蛋白Aster-C的强效和选择性抑制剂，该抑制剂对非天然甾醇AB环立体化学表现出惊人的偏好，同时还鉴定出了Aster-A的新型抑制剂。我们认为，这一策略能够且应该应用于任何与治疗相关的甾醇结合蛋白。
