Novel Targets for GPCR Drug Discovery: The Transmembrane Regions of GPCR Dimers

GPCRs: Important Therapeutic Targets

The largest superfamily of cell-membrane receptors, GPCRs, mediate several physiological and pathological processes, including humoral balance, energy metabolism, angiogenesis, cardiovascular control, and the neuroendocrine stress response. Consequently, 30–50% of clinical medications currently on the market target GPCRs, making them significant pharmacological targets. According to available data, GPCRs can form physiologically active dimers that control physiological and pathological processes by modulating particular signal transduction pathways. GPCR dimers are important research fields and emerging therapeutic targets because of their roles in pathogenic functions.

Functional Selectivity of GPCR Dimers

According to the traditional paradigm of GPCR pharmacology, ligands have single activation mechanism through which they work. Receptor ligands can be classified as full antagonists, partial agonists, antagonists, or reverse inverse agonists, depending on how effective they are. Nevertheless, ligands exhibit qualitative variations in functional selectivity in addition to quantitative variations. In other hands, a ligand can steer a given GPCR's signaling in the direction of a certain signal transduction pathway. These two routes can be "functionally selectively" activated or inactivated by a GPCR, each of which has a distinct downstream reaction. GPCRs can also maintain distinct activation states. After GPCR dimers develop, many biased ligands and receptors acquire bias; the dimers themselves are biased receptors, according to numerous research on the functional selectivity of dimers. The scientific community is paying close attention to the functional selectivity of GPCR dimers, which is a crucial aspect of GPCR pharmacology.

Fig.1. GPCR dimer formation.¹

Transmembrane Domain of GPCRs and Interfaces of GPCR Dimers

The structure is still up for debate, despite mounting experimental data supporting GPCR dimers and their functional importance. Studies of several GPCRs using disulfide bond crosslinking, atomic force microscopy, bioinformatics, and computational biology have revealed that significant structural factors seem to control receptor-dimer interactions, and that the interface mediates receptor-receptor interactions that are involved in the formation of GPCR complexes. Understanding the exact structure of GPCR dimers will help develop structure-dependent drug design and advance our knowledge of the function of receptor oligomerization in physiology, disease, and intercellular communication.

Transmembrane Domain Peptides: Candidates for Drug Development

Considered a crucial aspect of GPCR pharmacology, the skewed signal transduction route of GPCR dimers has garnered significant interest. GPCR dimer-biased ligands may offer a fresh approach to creating medications with minimal adverse effects. According to recent research, peptides originating from the transmembrane region of GPCRs interact with the GPCR, engage in binding competition with other GPCRs, and so prevent the formation of dimers and modify their activity. The receptor–receptor interface in cells must be identified in order to investigate the formation of GPCR dimers.

Creative Biolabs' Services of GPCRs

About 34% of all FDA-approved medications target the GPCR family, making them a significant target for pharmaceuticals. It is estimated that over 50% of pharmaceuticals now available on the market target GPCRs. Creative Biolabs provides GPCR drug discovery services for both academic and clinical use. Please contact us for more details about our GPCR drug discovery services. Our experts will help design an optimal solution for your project.

Reference

1. Lin, Huilan, et al. "Cofactoring and dimerization of proteinase-activated receptors." Pharmacological reviews 65.4 (2013): 1198-1213.