Scherer Manuel, Santana Andrés G, Robinson Kyle, Zhou Steven, Overkleeft Hermen S, Clarke Lorne, Withers Stephen G
Dept. of Chemistry. University of British Columbia Vancouver British Columbia V6T 1Z1 Canada
Dept. of Medical Genetics. University of British Columbia Vancouver British Columbia V6H 3N1 Canada.
Chem Sci. 2021 Sep 20;12(41):13909-13913. doi: 10.1039/d1sc03831a. eCollection 2021 Oct 27.
Gaucher's disease, the most prevalent lysosomal storage disorder, is caused by missense mutation of the GBA gene, ultimately resulting in deficient GCase activity, hence the excessive build-up of cellular glucosylceramide. Among different therapeutic strategies, pharmacological chaperoning of mutant GCase represents an attractive approach that relies on small organic molecules acting as protein stabilizers. Herein, we expand upon a new class of transient GCase inactivators based on a reactive 2-deoxy-2-fluoro-β-d-glucoside tethered to an array of lipid-mimicking phosphorus-based aglycones, which not only improve the selectivity and inactivation efficiency, but also the stability of these compounds in aqueous media. This hypothesis was further validated with kinetic and cellular studies confirming restoration of catalytic activity in Gaucher cells after treatment with these pharmacological chaperones.
戈谢病是最常见的溶酶体贮积症，由GBA基因的错义突变引起，最终导致葡糖脑苷脂酶（GCase）活性不足，从而使细胞内葡萄糖神经酰胺过度积累。在不同的治疗策略中，对突变型GCase进行药物伴侣介导是一种有吸引力的方法，该方法依赖于作为蛋白质稳定剂的小分子有机化合物。在此，我们扩展了一类基于与一系列模拟脂质的磷基糖苷配基相连的反应性2-脱氧-2-氟-β-D-葡萄糖苷的新型瞬时GCase失活剂，这些失活剂不仅提高了选择性和失活效率，还提高了这些化合物在水性介质中的稳定性。动力学和细胞研究进一步验证了这一假设，证实用这些药物伴侣处理后，戈谢细胞中的催化活性得以恢复。
