MRGPRX4 mediates phospho-drug-associated pruritus in a humanized mouse model

Area of Science:

• Pharmacology
• Neuroscience
• Structural Biology

Background:

• Phosphate modification enhances drug solubility for parenteral administration.
• Phosphate-modified drugs often cause dose-limiting pruritus via an unknown mechanism.

Purpose of the Study:

• To identify the molecular target responsible for phosphate-modified drug-induced itch.
• To elucidate the mechanism of interaction between phosphate-modified drugs and their target.
• To explore MRGPRX4 as a therapeutic target for managing drug-induced itch.

Main Methods:

• High-throughput drug screening to identify potential itch targets.
• G protein-coupled receptor (GPCR) assays (calcium mobilization, G protein-independent).
• Development of a humanized mouse model expressing MRGPRX4.
• Single-particle cryo-electron microscopy (cryo-EM) for structural determination.

Main Results:

• Mas-related G protein-coupled receptor X4 (MRGPRX4) was identified as a key target.
• Phosphate-modified compounds were found to potently activate MRGPRX4.
• A humanized mouse model demonstrated MRGPRX4-mediated itch in response to phosphomonoester prodrugs.
• Cryo-EM revealed the structure of MRGPRX4 bound to a phosphate-modified drug, identifying critical binding residues.

Conclusions:

• MRGPRX4 activation by phosphate-modified drugs explains the mechanism of drug-induced itch.
• MRGPRX4 is a potential therapeutic target for suppressing pruritus.
• Understanding this interaction can guide the design of future drugs with reduced itch side effects.