AI Article Synopsis
- Adhesion G protein-coupled receptors (aGPCRs) are a unique subgroup of the GPCR superfamily characterized by large, multi-domain N termini and the ability to undergo autoproteolytic cleavage.
- Despite the established role of GPCRs in pharmacology, no therapies targeting the 33 aGPCR members have been approved or are in clinical trials, although their link to various diseases is becoming clearer.
- The discussion highlights the potential for drug discovery in aGPCRs, focusing on challenges like target identification and validation, and outlines a framework for developing modulators, exemplified by ADGRG1.
Article Abstract
Adhesion G protein-coupled receptors (aGPCRs) - one of the five main families in the GPCR superfamily - have several atypical characteristics, including large, multi-domain N termini and a highly conserved region that can be autoproteolytically cleaved. Although GPCRs overall have well-established pharmacological tractability, currently no therapies that target any of the 33 members of the aGPCR family are either approved or in clinical trials. However, human genetics and preclinical research have strengthened the links between aGPCRs and disease in recent years. This, together with a greater understanding of their functional complexity, has led to growing interest in aGPCRs as drug targets. A framework for prioritizing aGPCR targets and supporting approaches to develop aGPCR modulators could therefore be valuable in harnessing the untapped therapeutic potential of this family. With this in mind, here we discuss the unique opportunities and challenges for drug discovery in modulating aGPCR functions, including target identification, target validation, assay development and safety considerations, using ADGRG1 as an illustrative example.
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| http://dx.doi.org/10.1038/s41573-019-0039-y | DOI Listing |
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