GPR52 is an orphan G protein-coupled receptor (GPCR) highly expressed in the brain, especially in the striatum, and represents an emerging therapeutic target for Huntington’s disease (HD), an incurable monogenic neurodegenerative disorder caused by the mutation of the huntingtin (mHTT) gene. This Viewpoint discusses the discovery, published in this journal, that a highly potent and specific GPR52 antagonist was identified through high-throughput screening and structure–activity relationship study, which diminishes not only mHTT protein levels, but also ameliorates HD-like phenotypes in the animal disease models. This strategy offers intriguing promise as a surprising approach for HD therapy, where nucleic acid medicine approaches such as small interference RNAs have been the main focus and encounter obstacles such as delivery efficiency.

中文翻译：

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发现第一种可治疗亨廷顿氏病的可药用GPR52拮抗剂

GPR52是在大脑特别是纹状体中高表达的孤儿G蛋白偶联受体（GPCR），它代表亨廷顿氏病（HD）的新兴治疗靶点，亨廷顿氏病（HD）是由亨廷顿蛋白（mHTT）突变引起的无法治愈的单基因神经退行性疾病）基因。该观点讨论了发表在该杂志上的发现，即通过高通量筛选和结构-活性关系研究确定了一种高效且特异的GPR52拮抗剂，不仅减少了mHTT蛋白水平，而且改善了HD样表型。动物疾病模型。这种策略为HD治疗带来了令人惊讶的前景，它是一种令人惊讶的HD治疗方法，其中核酸药物方法（例如小干扰RNA）已成为主要关注点，并遇到了传递效率等障碍。