Druggable Lipid GPCRs: Past, Present, and Prospects

Area of Science:

• Biochemistry
• Pharmacology
• Molecular Biology

Background:

• G protein-coupled receptors (GPCRs) are the largest human receptor superfamily, crucial for cellular signaling and drug discovery.
• GPCRs bind diverse endogenous ligands, including lipids, mediating various physiological and pathophysiological responses.
• Targeting lipid GPCRs offers significant therapeutic potential due to their involvement in numerous diseases.

Purpose of the Study:

• To systematically organize and understand druggable lipid GPCRs using a 'tidying up' approach.
• To consolidate information on lipid GPCRs, their ligands, and associated drugs from literature and databases.
• To explore innovative drug design strategies for lipid GPCRs to enhance efficacy and specificity.

Main Methods:

• A comprehensive review and consolidation of known lipid GPCRs, categorizing receptors for various lipid mediators.
• Literature and database mining to identify and categorize existing and investigational drugs targeting lipid GPCRs.
• Analysis of advanced drug design modalities, including allosteric modulators, biased agonism, and monoclonal antibodies.

Main Results:

• Consolidated 46 distinct lipid GPCRs, clarifying several previously perplexing receptors.
• Identified 24 marketed drugs targeting 16 unique lipid GPCRs, with 44 additional drugs in clinical trials as of 2019.
• Highlighted novel drug design strategies like PAMs, NAMs, biased agonism, and MAbs for improved therapeutic outcomes.

Conclusions:

• The systematic organization of lipid GPCRs and their drugs provides a clearer landscape for drug discovery.
• Current drug development focuses on 16 lipid GPCRs, with significant potential for novel therapeutics.
• Future technological advancements promise the discovery of new lipid ligands and the development of next-generation lipid GPCR drugs for diverse diseases.