Functional rescue and AI analysis of a human inactivating GPCR mutation using a small molecule.

Area of Science:

• Endocrinology
• Molecular Biology
• Pharmacology

Background:

• G protein-coupled receptors (GPCRs) are crucial for cellular signaling, and their mutations often lead to misfolding and trafficking defects, contributing to various diseases.
• Pharmacological chaperones (PCs) offer a potential therapeutic strategy by restoring proper folding and function to mutant GPCRs, though in vivo validation is limited.

Purpose of the Study:

• To evaluate the in vivo efficacy of a known pharmacological chaperone (PC) in rescuing function in a mouse model with a human luteinizing hormone receptor (LHR) mutation.
• To demonstrate the potential of repurposing small molecule GPCR ligands as therapeutic agents for GPCR-related pathologies.

Main Methods:

• Utilized a mouse model harboring an inactivating human LHR mutation.
• Administered a specific PC (Org42599/Org43553) to assess its effect on LHR signaling and reproductive function in mutant mice.
• Developed and employed an Artificial Intelligence (AI) algorithm for quantitative analysis of treatment efficacy and group differentiation.

Main Results:

• Mutant male mice exhibited delayed puberty and impaired Leydig cell LHR signaling, but fertility remained unaffected.
• Mutant female mice displayed irregular estrous cycles, anovulation, abrogated ovarian LHR signaling, and infertility.
• PC treatment successfully restored LHR signaling and normalized estrous cyclicity in mutant female mice.

Conclusions:

• Pharmacological chaperones can functionally rescue inactivating mutations in the luteinizing hormone receptor in vivo.
• The integration of AI-driven analysis with PC-based therapies presents a promising strategy for treating a wide range of GPCR-mediated diseases.
• This study provides a proof-of-concept for using PCs and AI to address genetic disorders affecting GPCRs.