2. Academic Validation
  3. A peptide display system identifies a potent mutant β-melanocyte-stimulating hormone agonist of melanocortin-4 receptor

A peptide display system identifies a potent mutant β-melanocyte-stimulating hormone agonist of melanocortin-4 receptor

  • Cell Genom. 2025 Sep 9:100988. doi: 10.1016/j.xgen.2025.100988.
Ann Lin 1,  Kaitlyn Spees 1,  Raeline Valbuena 1,  Jakob Wirbel 2,  Aravind Natarajan 2,  Nora Enright 3,  Ami S Bhatt 4,  Michael C Bassik 5
Affiliations

Affiliations

  • 1 Department of Genetics, Stanford University, Stanford, CA, USA.
  • 2 Department of Medicine, Division of Hematology, Stanford University, Stanford, CA, USA.
  • 3 Department of Bioengineering, Stanford University, Stanford, CA, USA.
  • 4 Department of Genetics, Stanford University, Stanford, CA, USA; Department of Medicine, Division of Hematology, Stanford University, Stanford, CA, USA. Electronic address: asbhatt@stanford.edu.
  • 5 Department of Genetics, Stanford University, Stanford, CA, USA. Electronic address: bassik@stanford.edu.
PMID: 40930102 DOI: 10.1016/j.xgen.2025.100988
Abstract

Non-olfactory G-protein-coupled receptors (GPCRs) regulate vital physiological functions and are targets for ∼34% of US Food and Drug Administration (FDA)-approved drugs. While small-molecule-activated GPCRs are well studied, there is growing interest in peptide GPCRs, particularly the melanocortin-4 receptor (MC4R), a key regulator of energy balance and appetite. Activation of MC4R by β-melanocyte-stimulating hormone (β-MSH) reduces food intake, and pathway dysfunction leads to obesity. However, current methods to study GPCR-peptide interactions are resource intensive and low throughput. To address this, we developed a high-throughput cell surface peptide display platform with a β-arrestin-based MC4R reporter to screen over 2,000 β-MSH point mutants. This approach identified peptide variants that significantly impact MC4R activation, including a novel D5H mutant with enhanced receptor activation. Our results demonstrate a scalable method to directly link GPCR activation to peptide variants, offering insights for therapeutic peptide design.

Keywords

MC4R; peptide display; scanning mutagenesis.

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