Accelerating GPCR Drug Discovery With Conformation-Stabilizing VHHs

Area of Science:

• Biochemistry and structural biology
• Pharmacology and drug discovery
• Molecular and cellular biology

Background:

• G protein-coupled receptors (GPCRs) are crucial drug targets, with 40% of marketed drugs modulating them.
• Significant potential exists for targeting the 60% of non-olfactory GPCRs lacking clinical candidates.
• Conventional high-throughput screening (HTS) for GPCRs faces challenges due to low success rates and difficulties in structure determination.

Purpose of the Study:

• To review the application of camelid-derived immunoglobulin single variable domains (VHHs), termed ConfoBodies, for stabilizing GPCRs.
• To highlight how ConfoBodies accelerate drug discovery by enabling better understanding of GPCR pharmacology and structure.
• To demonstrate the impact of ConfoBodies on translational research through active state screening and structure-informed drug design.

Main Methods:

• Utilizing VHHs (ConfoBodies) to stabilize specific GPCR conformations and GPCR:signal transducer complexes.
• Employing stabilized GPCRs for enhanced in vitro screening assays.
• Applying structural biology techniques to ConfoBody-stabilized GPCRs for structure-based drug design.

Main Results:

• ConfoBodies effectively stabilize disease-relevant GPCR states and complexes.
• These stabilized targets facilitate improved screening and deconvolution of complex GPCR pharmacology.
• Structure-informed design using ConfoBody-stabilized GPCRs enables identification of novel chemical matter with improved potency and selectivity.

Conclusions:

• ConfoBodies are powerful tools for overcoming challenges in GPCR drug discovery.
• They significantly enhance the efficiency of screening campaigns and structure-based rational design.
• ConfoBodies hold substantial promise for accelerating the development of novel therapeutics targeting GPCRs.