Discovery of the First Druggable GPR52 Antagonist to Treat Huntington's Disease

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.

Automated summary

The discovery of a highly potent and specific GPR52 antagonist through high-throughput screening and structure-activity relationship study offers promising potential as a novel therapeutic approach for Huntington's disease. This strategy not only reduces mHTT protein levels, but also ameliorates HD-like phenotypes in animal disease models, providing a new direction in HD therapy compared to traditional nucleic acid medicine approaches.