曲美他嗪可作为 MPS I-H（黏多糖贮积症 I-H 型）有效的无义抑制药物。

Triamterene Functions as an Effective Nonsense Suppression Agent for MPS I-H (Hurler Syndrome).

机构信息

Department of Biochemistry & Molecular Genetics, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

Next Generation Sequencing Transplant Diagnostics, Thermo-Fisher Scientific, West Hills, CA 91304, USA.

出版信息

Int J Mol Sci. 2023 Feb 24;24(5):4521. doi: 10.3390/ijms24054521.

DOI:10.3390/ijms24054521

PMID:36901952

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10003437/

Abstract

Mucopolysaccharidosis I-Hurler (MPS I-H) is caused by the loss of α-L-iduronidase, a lysosomal enzyme that degrades glycosaminoglycans. Current therapies cannot treat many MPS I-H manifestations. In this study, triamterene, an FDA-approved, antihypertensive diuretic, was found to suppress translation termination at a nonsense mutation associated with MPS I-H. Triamterene rescued enough α-L-iduronidase function to normalize glycosaminoglycan storage in cell and animal models. This new function of triamterene operates through premature termination codon (PTC) dependent mechanisms that are unaffected by epithelial sodium channel activity, the target of triamterene's diuretic function. Triamterene represents a potential non-invasive treatment for MPS I-H patients carrying a PTC.

摘要

黏多糖贮积症 I 型 Hurler 型（MPS I-H）是由于α-L-艾杜糖苷酸酶的缺失引起的，该酶是一种溶酶体酶，可降解糖胺聚糖。目前的治疗方法无法治疗 MPS I-H 的许多表现。在这项研究中，发现一种已获得 FDA 批准的抗高血压利尿剂曲美他嗪可抑制与 MPS I-H 相关的无意义突变的翻译终止。曲美他嗪挽救了足够的α-L-艾杜糖苷酸酶功能，使细胞和动物模型中的糖胺聚糖储存恢复正常。曲美他嗪的这种新功能通过提前终止密码子（PTC）依赖性机制发挥作用，不受曲美他嗪利尿功能的靶标上皮钠通道活性的影响。曲美他嗪为携带 PTC 的 MPS I-H 患者提供了一种潜在的非侵入性治疗方法。