Setmelanotide (IMCIVREE): Molecular Structure

Molecular Overview#

Setmelanotide (IMCIVREE) is a synthetic cyclic octapeptide designed to selectively activate the melanocortin-4 receptor (MC4R). Its structure incorporates several key design features that optimize receptor binding, selectivity, and metabolic stability.

Structural Design#

The molecular engineering of setmelanotide includes several critical modifications:

1. Cyclic backbone: A disulfide bridge between Cys2 and Cys8 constrains the peptide into a ring structure, positioning the melanocortin pharmacophore for optimal MC4R engagement
2. Melanocortin pharmacophore: The His-D-Phe-Arg-Trp sequence (positions 4-7) is the essential binding motif for melanocortin receptors, derived from the natural alpha-MSH peptide
3. D-amino acids: D-Ala at position 3 and D-Phe at position 5 resist proteolytic enzymes, extending the half-life and enabling once-daily dosing
4. Terminal modifications: N-terminal acetylation and C-terminal amidation protect against exopeptidases and improve stability

Physical and Chemical Properties#

Pharmacokinetics#

Setmelanotide has a half-life of approximately 11 hours following subcutaneous injection, supporting once-daily dosing. Peak plasma concentrations are reached approximately 8 hours after injection. The relatively long half-life for a small peptide is achieved through the combined effects of the cyclic structure, D-amino acids, and terminal modifications that protect against enzymatic degradation.

Melanocortin Receptor Selectivity#

Setmelanotide is designed as an MC4R agonist but retains activity at other melanocortin receptors, which explains some of its side effects:

The MC1R cross-reactivity is responsible for the skin hyperpigmentation observed in the majority of setmelanotide-treated patients. This is a pharmacological effect of melanocortin receptor activation on melanocytes and is generally reversible upon discontinuation.

Molecular Context#

Setmelanotide (IMCIVREE) belongs to the Metabolic category of research peptides. The molecular properties of Setmelanotide (IMCIVREE) determine its pharmacological behavior, including receptor binding, distribution, metabolism, and elimination. Understanding these properties is fundamental to interpreting clinical data and designing research protocols.

Structural Overview#

Setmelanotide (IMCIVREE) is characterized as: Setmelanotide is a cyclic 8-amino acid peptide with a molecular weight of 1,117.31 Da. The cyclic structure is formed by a disulfide bridge between Cys2 and Cys8, constraining the pharmacophore for optimal MC4R binding. The peptide contains two D-amino acids (D-Ala at position 3 and D-Phe at position 5) that confer resistance to proteolytic degradation. The His-D-Phe-Arg-Trp core sequence represents the melanocortin pharmacophore essential for MC4R activation. N-terminal acetylation and C-terminal amidation further enhance metabolic stability..

Amino Acid Sequence Details#

The amino acid sequence of Setmelanotide (IMCIVREE) is: Ac-Arg-Cys-D-Ala-His-D-Phe-Arg-Trp-Cys-NH2. Eight amino acids in a cyclic structure formed by a disulfide bridge between Cys2 and Cys8. Contains two D-amino acids (D-Ala3, D-Phe5) for protease resistance. N-terminal acetylated, C-terminal amidated.. This sequence determines the peptide's three-dimensional structure, receptor binding properties, and biological activity.

Pharmacokinetic Profile#

Half-Life: ~11 hours, supporting once-daily subcutaneous injection

The half-life of a peptide influences dosing frequency, duration of effect, and the clinical utility of the compound. Researchers should consider the half-life when designing experimental protocols.

Related Reading#

• Setmelanotide (IMCIVREE) overview and research guide
• Peptides similar to Setmelanotide (IMCIVREE)
• Setmelanotide (IMCIVREE) research evidence