通过高内容选方法识别交通缺陷的ABCB4变体的新校正器
Mounia Lakli1, Julie Dumont2,3, Virginie Vauthier4
1Inserm, Université Paris-Saclay, Physiopathogénèse et traitement des maladies du foie, UMR_S 1193, Hepatinov, F-91400, Orsay, France.
Communications biology
|July 24, 2024
概括
研究人员确定了可以纠正ABCB4转运器缺陷的小分子,为3型进展性家族性肝内胆固醇症 (PFIC3) 和其他罕见肝病提供了潜在的新疗法.
科学领域:
- 肝病学 肝病学是一种肝病学.
- 分子生物学分子生物学
- 药物发现 药物发现 药物发现
背景情况:
- 在肝细胞中,ABCB4转运体对酸丁胆分泌至关重要.
- 遗传ABCB4变异导致罕见的胆固醇性肝脏疾病,如进展性家族性肝脏内胆固醇症3型 (PFIC3),往往需要肝移植.
- 对于严重的ABCB4相关肝脏疾病的替代治疗方法,存在重大未满足的医疗需求.
研究的目的:
- 开发一种高含量选方法,以识别能够纠正ABCB4分子缺陷的小分子.
- 在细胞模型中评估已识别的小分子在恢复ABCB4蛋白质成熟,局部化和功能方面的有效性.
主要方法:
- 细胞模型中细胞内保留的ABCB4变体的表达.
- 高含量查以确定潜在的治疗分子.
- 分析ABCB4成熟,细胞局部化和治疗后的功能.
- 在基分子对接以预测药物标相互作用.
主要成果:
- 通过高含量查确定了六种有前途的小分子.
- 三个分子纠正了细胞内ABCB4变异的成熟和状局部.
- 一个分子显著恢复了两个ABCB4变体的功能.
- 分子对接表明与ABCB4的ATP结合部位的相互作用.
结论:
- 鉴定到的小分子显示出在肝细胞中纠正ABCB4缺陷的潜力.
- 这些发现为开发用于治疗严重的ABCB4相关肝病的新型候选药物提供了基础,包括PFIC3.
- 开发的查方法和识别的成功结果可能为肝移植提供了替代方案.
相关概念视频
01:31ABC Transporters: Exporter
ATP-binding cassette or ABC transporter is the largest superfamily of integral membrane proteins. The transporters have transmembrane-binding domains (TMDs) and nucleotide-binding domains (NBDs). The TMDs are specific to their substrates, whereas the NBDs are similar to engines that complete ATP hydrolysis to complete the substrate transport. They can be full transporters consisting of two TMDs and NBDs, half transporters with one TMD and NBD, while some encoded with a single TMD or NBD are...
01:27ABC Transporters: Importer
ATP-binding cassette or ABC transporters are a class of ATP-driven pumps that hydrolyze ATP to move solutes across the membrane. They can be grouped into importers and exporters. While exporters are present in all domains of life, importers exist only in bacteria and some plants.
In bacteria, based on the number of transmembrane helices and the chemical nature of their substrates, the ABC importers can be divided into three types:
In bacteria, based on the number of transmembrane helices and the chemical nature of their substrates, the ABC importers can be divided into three types: