Afamelanotide: Molecular Structure

Molecular Structure#

Afamelanotide has the molecular formula C78H111N21O19 and a molecular weight of approximately 1646.85 Da. It is a synthetic tridecapeptide that is structurally based on the 13-amino acid alpha-melanocyte-stimulating hormone (alpha-MSH) with two critical amino acid substitutions.

Amino Acid Sequence#

Afamelanotide: Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2

Native alpha-MSH: Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2

The two modifications are:

1. Position 4: Met to Nle (norleucine): Prevents methionine oxidation, which would inactivate the peptide. Norleucine is isosteric with methionine but lacks the sulfur atom susceptible to oxidation.
2. Position 7: L-Phe to D-Phe: The D-amino acid substitution dramatically enhances MC1R binding affinity and provides resistance to enzymatic degradation by proteases that specifically cleave L-amino acid bonds.

Design Rationale#

The [Nle4, D-Phe7] substitution pattern was pioneered by Victor Hruby and colleagues at the University of Arizona. These modifications collectively make afamelanotide a "superpotent" MC1R agonist with:

• 10-100x greater potency than native alpha-MSH
• Extended biological activity due to protease resistance
• Enhanced stability from elimination of oxidation-prone methionine
• Maintained selectivity for MC1R over other melanocortin receptors

Chemical Properties#

Implant Formulation#

Afamelanotide is administered as a subcutaneous bioresorbable implant rather than a standard injection. The implant consists of 16 mg afamelanotide in a poly(D,L-lactide-co-glycolide) (PLGA) matrix approximately 1.7 cm in length and 1.45 mm in diameter. The PLGA matrix provides controlled release of the peptide over approximately 60 days as the polymer degrades.

Melanocortin Receptor Selectivity#

While afamelanotide is primarily an MC1R agonist, it has some activity at other melanocortin receptors. Compared to Melanotan II (a cyclic heptapeptide), afamelanotide is more selective for MC1R and has reduced activity at MC3R, MC4R, and MC5R, resulting in fewer off-target effects.

Molecular Context#

Afamelanotide belongs to the Skin category of research peptides. The molecular properties of Afamelanotide 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#

Afamelanotide is characterized as: Afamelanotide is a 13-amino acid linear peptide analog of alpha-MSH with two key modifications. Norleucine replaces methionine at position 4 (preventing oxidation) and D-phenylalanine replaces L-phenylalanine at position 7 (enhancing receptor binding and metabolic stability). These changes confer superpotent MC1R agonist activity..

Amino Acid Sequence Details#

The amino acid sequence of Afamelanotide is: Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2. This sequence determines the peptide's three-dimensional structure, receptor binding properties, and biological activity.

Pharmacokinetic Profile#

Half-Life: Approximately 15 hours (from subcutaneous implant with sustained release over 60 days)

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#

• Afamelanotide overview and research guide
• Peptides similar to Afamelanotide
• Afamelanotide research evidence