Technologies for the discovery of G protein–coupled receptor–targeting biologics

• Published in: Current opinion in biotechnology 2024-06, Vol.87, p.103138, Article 103138
• Main Authors: Downey, McKenna L, Peralta-Yahya, Pamela
• Format: Article
• Language: English
• Subjects: Biological Products - metabolism; Drug Discovery - methods; Humans; Protein Engineering - methods; Receptors, G-Protein-Coupled - metabolism; Synthetic Biology - methods
• ISSN: 0958-1669; 1879-0429; 1879-0429
• DOI: 10.1016/j.copbio.2024.103138

G protein–coupled receptors (GPCRs) are important pharmaceutical targets, working as entry points for signaling pathways involved in metabolic, neurological, and cardiovascular diseases. Although small molecules remain the major GPCR drug type, biologic therapeutics, such as peptides and antibodies, are increasingly found among clinical trials and Food and Drug Administration (FDA)-approved drugs. Here, we review state-of-the-art technologies for the engineering of biologics that target GPCRs, as well as proof-of-principle technologies that are ripe for this application. Looking ahead, inexpensive DNA synthesis will enable the routine generation of computationally predesigned libraries for use in display assays for the rapid discovery of GPCR binders. Advances in synthetic biology are enabling the increased throughput of functional GPCR assays to the point that they can be used to directly identify biologics that modulate GPCR activity. Finally, we give an overview of adjacent technologies that are ripe for application to discover biologics that target human GPCRs. •Biologics are increasingly found among clinical trials and FDA approved drugs targeting GPCRs.•Biologics that modulate GPCR's activity are difficult to discover due to GPCRs' buried orthosteric site.•GPCR functional assays allow for direct identification of biologics that modulate GPCR activity.•Co-encoding GPCR functional assays and biologics libraries foresees the evolution of GPCR-targeting biologics.