Towards selective lysophospholipid GPCR modulators

• We outline the importance of the lysophospholipid GPCRs as drug targets.
• We highlight the challenges in developing selective modulators of these receptors.
• We outline the currently available selective modulators targeting some of the receptor subtypes.
• We touch on the recent structure of the Edg lipid GPCR (S1PR1), but highlight the need for a representative structure of a non-Edg-like GPCR family member.
• Targeting the non-conserved allosteric binding sites of these lipid GPCRs shows particular promise for the development of selective modulators by structure-based drug design.

G-protein-coupled receptors (GPCRs) that recognize the lysophospholipids (LPLs) are grouped into two phylogenetically distinct families: the endothelial differentiation gene (Edg) and non-Edg GPCRs. Owing to their more recent identification, and hindered by a lack of selective pharmacological tools, our understanding of the functions and signaling pathways of the non-Edg GPCRs is still in its infancy. Targeting the non-conserved allosteric binding sites of the LPL GPCRs shows particular promise for the development of selective modulators by structure-based drug design. However, only one Edg GPCR (S1PR1) structure has been determined to date, and it has low sequence identity with the non-Edg GPCRs (<20%). Thus, a representative structure of a non-Edg GPCR remains a pressing objective for selective structure-based drug design. Obtaining selective modulators targeting the non-Edg receptors would help to unravel the biology behind these novel GPCRs and potentially will support therapeutic treatment of diseases such as cancer, inflammation, and neuropsychiatric disorders.