From a Cone Snail Toxin to a Competitive MC4R Antagonist

Area of Science:

• Biochemistry
• Pharmacology
• Neuroendocrinology

Background:

• The melanocortin 4 receptor (MC4R) is crucial for energy homeostasis and a therapeutic target for obesity.
• Current MC4R ligands are synthetic, but animal venoms offer a novel source of bioactive compounds.

Purpose of the Study:

• To identify and characterize novel MC4R ligands from natural sources.
• To explore the potential of venom-derived peptides as therapeutic agents for energy balance disorders.

Main Methods:

• Screening of cone snail venom for MC4R binding activity.
• Characterization of the identified toxin N-CTX-Ltg1a and its derived peptide HT1-0.
• Assessing HT1-0's antagonist activity across multiple signaling pathways (Gs, G15, β-arrestin2).

Main Results:

• Discovery of N-CTX-Ltg1a, a cone snail toxin with nanomolar affinity for hMC4R, unrelated to known toxins.
• Development of the linear peptide HT1-0 from N-CTX-Ltg1a.
• HT1-0 functions as a competitive antagonist for Gs, G15, and β-arrestin2 pathways with low nanomolar affinity for hMC4R.
• HT1-0 binding requires hydrophobic and basic residues, similar to endogenous ligands.

Conclusions:

• HT1-0 is the first high-affinity MC4R antagonist derived from venom.
• This discovery provides a new scaffold for developing innovative MC4R antagonists.
• Venom-derived peptides represent a promising resource for novel therapeutic agents targeting MC4R.