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Bromocriptine as a Novel Pharmacological Chaperone for Mucopolysaccharidosis IV A.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-06-24 , DOI: 10.1021/acsmedchemlett.0c00042 Sergio Olarte-Avellaneda 1, 2 , Jacobo Cepeda Del Castillo 1 , Andrés Felipe Rojas-Rodriguez 3 , Oscar Sánchez 4 , Alexander Rodríguez-López 1, 5 , Diego A Suárez García 1, 6 , Luz Mary Salazar Pulido 7 , Carlos J Alméciga-Díaz 1
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-06-24 , DOI: 10.1021/acsmedchemlett.0c00042 Sergio Olarte-Avellaneda 1, 2 , Jacobo Cepeda Del Castillo 1 , Andrés Felipe Rojas-Rodriguez 3 , Oscar Sánchez 4 , Alexander Rodríguez-López 1, 5 , Diego A Suárez García 1, 6 , Luz Mary Salazar Pulido 7 , Carlos J Alméciga-Díaz 1
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Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disease caused by mutations in the gene encoding for the enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS), leading to lysosomal accumulation of keratan sulfate (KS) and chondroitin-6-sulfate. In this study, we identified and characterized bromocriptine (BC) as a novel PC for MPS IVA. BC was identified through virtual screening and predicted to be docked within the active cavity of GALNS in a similar conformation to that observed for KS. BC interacted with similar residues to those predicted for natural GALNS substrates. In vitro inhibitory assay showed that BC at 50 μM reduced GALNS activity up to 30%. However, the activity of hrGALNS produced in HEK293 cells was increased up to 1.48-fold. BC increased GALNS activity and reduced lysosomal mass in MPS IVA fibroblasts in a mutation-dependent manner. Overall, these results show the potential of BC as a novel PC for MPS IVA and contribute to the consolidation of PCs as a potential therapy for this disease.
中文翻译：
溴隐亭作为黏多糖贮积症IV A的新型药理伴侣。
粘多糖贮积症（IVS）是一种溶酶体贮积病，由N-乙酰半乳糖胺6-硫酸盐硫酸酯酶（GALNS）的编码基因突变引起，导致溶酶体积累硫酸角质素（KS）和软骨素6-硫酸盐。在这项研究中，我们确定并表征了溴隐亭（BC）作为MPS IVA的新型PC。通过虚拟筛选鉴定出BC，并预测其将以与KS观察到的相似构象停靠在GALNS的活动腔内。BC与与天然GALNS底物预测的残基相似的残基相互作用。体外抑制试验表明，浓度为50μM的BC可使GALNS活性降低30％。然而，在HEK293细胞中产生的hrGALNS的活性增加到1.48倍。BC以依赖突变的方式增加了MPS IVA成纤维细胞的GALNS活性，并减少了溶酶体质量。总体而言，这些结果显示了BC作为MPS IVA新型PC的潜力，并有助于巩固PC作为该疾病的潜在疗法。
更新日期：2020-07-09
中文翻译：
溴隐亭作为黏多糖贮积症IV A的新型药理伴侣。
粘多糖贮积症（IVS）是一种溶酶体贮积病，由N-乙酰半乳糖胺6-硫酸盐硫酸酯酶（GALNS）的编码基因突变引起，导致溶酶体积累硫酸角质素（KS）和软骨素6-硫酸盐。在这项研究中，我们确定并表征了溴隐亭（BC）作为MPS IVA的新型PC。通过虚拟筛选鉴定出BC，并预测其将以与KS观察到的相似构象停靠在GALNS的活动腔内。BC与与天然GALNS底物预测的残基相似的残基相互作用。体外抑制试验表明，浓度为50μM的BC可使GALNS活性降低30％。然而，在HEK293细胞中产生的hrGALNS的活性增加到1.48倍。BC以依赖突变的方式增加了MPS IVA成纤维细胞的GALNS活性，并减少了溶酶体质量。总体而言，这些结果显示了BC作为MPS IVA新型PC的潜力，并有助于巩固PC作为该疾病的潜在疗法。
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