5-C-支链脱氧野尻霉素：设计具有纳摩尔亲和力的庞贝病基于 1-脱氧野尻霉素的药理学伴侣的策略,Journal of Medicinal Chemistry

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5-C-支链脱氧野尻霉素：设计具有纳摩尔亲和力的庞贝病基于 1-脱氧野尻霉素的药理学伴侣的策略
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-01-24 , DOI: 10.1021/acs.jmedchem.1c01673
Atsushi Kato ₁ , Izumi Nakagome ₂ , Uta Kanekiyo ₁ , Tian-Tian Lu _{3,

4} , Yi-Xian Li _{3,

4} , Kosuke Yoshimura ₁ , Mana Kishida ₁ , Kenta Shinzawa ₁ , Tomoki Yoshida ₂ , Nobutada Tanaka ₂ , Yue-Mei Jia _{3,

4} , Robert J Nash ₅ , George W J Fleet ₆ , Chu-Yi Yu _{3,

4}

Affiliation

近年来，药理学伴侣作为“热力学稳定剂”的作用在联合治疗中备受关注。药理学伴侣和重组人酸性 α-葡萄糖苷酶 (rhGAA) 的共同给药通过与 rhGAA 的折叠状态结合来提高稳定性和成熟度，从而促进酶的递送。本研究提供了设计针对溶酶体酸 α-葡萄糖苷酶 (GAA) 的高亲和力配体的策略的第一个示例，重点是 1-脱氧野尻霉素 (DNJ) 上的烷基支链；5 - C-庚基-DNJ 对 GAA 产生纳摩尔亲和力，K _i值为 0.0047 μM，比 DNJ 强 13 倍。蛋白质热位移分析表明，10 μM 5- C-heptyl-DNJ 在没有配体的情况下将蛋白质变性温度 ( T _m ) 的中点从 58.6 °C 提高到 73.6 °C，显着提高了 rhGAA 的热稳定性。此外，5 - C-庚基-DNJ 剂量依赖性增加了具有 M519V 突变的 Pompe 患者的成纤维细胞中的细胞内 GAA 活性。在 DNJ 上引入 C5 烷基分支为庞贝病的药物伴侣治疗提供了新的分子策略，这可能导致更高亲和力和实用的伴侣的开发。

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5-C-Branched Deoxynojirimycin: Strategy for Designing a 1-Deoxynojirimycin-Based Pharmacological Chaperone with a Nanomolar Affinity for Pompe Disease

In recent years, the function of pharmacological chaperones as a “thermodynamic stabilizer” has been attracting attention in combination therapy. The coadministration of a pharmacological chaperone and recombinant human acid α-glucosidase (rhGAA) leads to improved stability and maturation by binding to the folded state of the rhGAA and thereby promotes enzyme delivery. This study provides the first example of a strategy to design a high-affinity ligand toward lysosomal acid α-glucosidase (GAA) focusing on alkyl branches on 1-deoxynojirimycin (DNJ); 5-C-heptyl-DNJ produced a nanomolar affinity for GAA with a K_i value of 0.0047 μM, which is 13-fold more potent than DNJ. The protein thermal shift assay revealed that 10 μM 5-C-heptyl-DNJ increased the midpoint of the protein denaturation temperature (T_m) to 73.6 °C from 58.6 °C in the absence of the ligand, significantly improving the thermal stability of rhGAA. Furthermore, 5-C-heptyl-DNJ dose dependency increased intracellular GAA activities in Pompe patient’s fibroblasts with the M519V mutation. The introduction of C5 alkyl branches on DNJ provides a new molecular strategy for pharmacological chaperone therapy for Pompe disease, which may lead to the development of higher-affinity and practically useful chaperones.

更新日期：2022-02-10

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