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Single Nucleotide Polymorphisms in the Melanocortin His-Phe-Arg-Trp Sequences Decrease Tetrapeptide Potency and

Marshall D Winget1, Mark D Ericson1, Katie T Freeman1

  • 1Department of Medicinal Chemistry & Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, United States.

ACS Medicinal Chemistry Letters
|March 19, 2020
PubMed

Insights

Genetic variations in proopiomelanocortin (POMC) signaling sequences reduce agonist effectiveness at melanocortin receptors. These POMC gene polymorphisms impact receptor activation, potentially affecting conditions like obesity and adrenal insufficiency.

Area of Science:

  • Biochemistry
  • Genetics
  • Pharmacology

Background:

  • Melanocortin receptors are activated by agonists derived from the proopiomelanocortin (POMC) gene.
  • A conserved His-Phe-Arg-Trp tetrapeptide sequence is crucial for POMC agonist activity.
  • POMC signaling deficiencies in humans are linked to adrenal insufficiency, pigmentation changes, and early-onset obesity.

Purpose of the Study:

  • To investigate the in vitro effects of single nucleotide polymorphisms (SNPs) within the POMC-derived His-Phe-Arg-Trp sequence on melanocortin receptor activation.
  • To determine how naturally occurring genetic variations impact the potency and efficacy of POMC-derived agonists.

Main Methods:

  • Identified 12 single nucleotide polymorphisms (SNPs) in the His-Phe-Arg-Trp sequences of POMC-derived agonists (ACTH, α-MSH, β-MSH, γ-MSH) from the Variation Viewer database.
  • Synthesized tetrapeptide analogs incorporating these SNPs.
  • Assayed the in vitro signaling activity of these modified peptides at cloned melanocortin receptors.

Main Results:

  • All 12 tested polymorphisms within the POMC tetrapeptide sequence reduced agonist potency and/or efficacy at the melanocortin receptors.
  • These findings demonstrate that genetic variations in this critical signaling motif impair receptor activation.

Conclusions:

  • Polymorphisms within the His-Phe-Arg-Trp sequence of POMC-derived agonists negatively impact melanocortin receptor activation.
  • Further research incorporating these substitutions into full-length POMC agonists is warranted.
  • These results may help identify patient populations benefiting from therapies for POMC-deficient signaling disorders.

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