Structure-guided design of a peripherally restricted chemogenetic system

Area of Science:

• Neuroscience
• Pharmacology
• Biochemistry

Background:

• Designer receptors exclusively activated by designer drugs (DREADDs) are vital chemogenetic tools for controlling cellular functions.
• Existing DREADDs may have limitations in targeting specific systems due to blood-brain barrier (BBB) penetration.

Purpose of the Study:

• To develop a peripherally restricted DREADD system for precise control of peripheral signaling.
• To create a novel chemogenetic tool that minimizes central nervous system (CNS) effects.

Main Methods:

• Structure-guided design and mutagenesis to create hydroxycarboxylic acid receptor DREADD (HCAD).
• Utilized an ultra-large make-on-demand library for analoging and identified a BBB-impermeable chemical actuator.
• Determined HCAD structure via cryo-electron microscopy (cryo-EM) and validated its function in dorsal root ganglion (DRG) neurons.

Main Results:

• Developed HCAD, a peripherally restricted Gi-DREADD with minimal native brain expression.
• HCAD activation in DRG neurons inhibited action potential firing.
• Demonstrated reduction in both acute and inflammatory pain models.

Conclusions:

• The HCAD system offers a novel method for studying peripheral systems with reduced CNS side effects.
• This structure-guided approach can accelerate the development of future chemogenetic tools for research and therapeutic applications.