Setmelanotide

1 Identity

Synthetic cyclic octapeptide, disulfide-bridged, doubly end-capped and containing two D-amino acids — which is why it sits in panel P3 rather than P1. N-terminally acetylated, C-terminally amidated, with an intramolecular Cys2-Cys8 disulfide closing a seven-residue macrocycle and Arg1 exocyclic to it. The two non-L residues are D-Ala at position 3 and D-Phe at position 5. Two sulfurs, both in the disulfide; three basic side chains (two Arg plus the imidazole of His); one tryptophan, which is the oxidation- and light-sensitive residue. and the active moiety of IMCIVREE. setmelanotide acetate (CAS 1504602-49-6, a distinct registry number for the salt). CAS 920014-72-8 for the free base. Not a melanotan: it is a different molecule from Melanotan II and from bremelanotide.

Sequence

Ac-Arg-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2, with the disulfide bridge between Cys2 and Cys8. Eight residues, N-acetylated, C-terminally amidated, one intramolecular disulfide. Written in the vendor convention: Ac-Arg-Cys-{D-Ala}-His-{D-Phe}-Arg-Trp-Cys-NH2 (Disulfide bridge: Cys2-Cys8). The D-configuration at positions 3 and 5 is part of the identity of the molecule and is not visible in any mass measurement.

Molecular formula

C49H68N18O9S2 (free base, oxidized and cyclized form). Two sulfurs, both consumed by the disulfide, so the reduced form is a different formula and a different mass.

Average mass

1117.320 Da (C49H68N18O9S2) on IUPAC 2021 abridged conventional atomic weights. Three independent sellers publish 1117.31 for the same formula; that figure is exactly what this formula returns on the pre-2021 table (1117.309), so the two numbers are one composition on two atomic-weight tables and not a discrepancy. The acetate salt has no single average mass: at 1 mol acetate the formula weight is 1177.37 (acetate 5.10 percent w/w), at 2 mol 1237.42 (9.71 percent), at 3 mol 1297.48 (13.89 percent). At this molecular size the counterion fraction is an order of magnitude more consequential than it is on a 3-4 kDa peptide, and no seller found publishes a stoichiometry.

Monoisotopic mass

1116.48581 Da neutral free base; [M+H]+ 1117.49308; [M+2H]2+ 559.25018. A plus or minus 5 ppm window on the protonated ion is plus or minus 0.0056 Da, which is well inside the 2.02 Da that separates the cyclized molecule from its reduced open-chain form and the 42.04 Da that separates it from the des-acetyl species. It is of no use whatever against the D-to-L epimers, which are isobaric to the last decimal.

Salt / variant note

Six confusables, and one of them cannot be detected by mass at all. (1) The reduced, open-chain dithiol, C49H70N18O9S2, 1119.336 avg / 1118.50146 mono — exactly +2.016 Da, and it is the failure mode that matters most for a disulfide-cyclized peptide, because an incorrectly folded or partially reduced lot is a different molecule with the same residues. Ellman assay and a non-reducing versus reducing chromatographic comparison settle it; intact mass sees the 2.02 Da if the resolution is adequate. (2) Disulfide-linked dimers and higher oligomers, which appear near twice the parent mass and are the classic aggregation-driven impurity class in cyclic peptides; size-exclusion or non-reducing SDS analysis is required because reversed-phase can co-elute them. (3) The D-to-L epimers at position 3 or position 5 — identical formula, identical mass to the last decimal, and no mass spectrometer at any resolving power distinguishes them. This is the single reason the article sits in panel P3 and the reason a chiral method is a release test rather than a characterization nicety. (4) Des-acetyl setmelanotide, C47H66N18O8S2, 1075.283 avg / 1074.47524 mono — 42.04 Da lighter, arising from incomplete N-terminal capping. (5) C-terminal free acid instead of the amide, C49H67N17O10S2, 1118.304 avg / 1117.46982 mono — 0.98 Da heavier and invisible on a nominal-mass instrument. (6) Tryptophan oxidation, +15.995, C49H68N18O10S2, 1133.319 avg / 1132.48072 mono. Neighboring melanocortin peptides sold on the same shelves and confusable by name rather than by mass: bremelanotide C50H68N14O10, 1025.182 avg / 1024.52428 mono, and Melanotan II C50H69N15O9, 1024.198 avg / 1023.54027 mono — note that those two are 0.98 Da apart from each other, so a certificate reading "1024" or "1025" identifies neither reliably. Bremelanotide is the name collision that actually occurs with this article, and it is a different molecule: the two are 92.14 Da apart, so any mass measurement of adequate resolution separates them. Salt arithmetic on setmelanotide: acetate 5.10 percent w/w at 1 mol, 9.71 percent at 2 mol, 13.89 percent at 3 mol; trifluoroacetate 9.26 percent at 1 mol and 16.95 percent at 2 mol. On a 1117 Da peptide with three basic centers, an undeclared 2:1 trifluoroacetate removes roughly a sixth of the peptide a buyer thinks is in the vial.

2 Class & testing panel

Form

Single article

Testing panel

P3 — panel definition

3 Primary sources & evidence

The index reports the design and provenance of the literature, not a conclusion about effect.

A substantial regulatory-grade human evidence base exists, and it belongs to the approved finished product and its sponsor program, not to bulk material of unverified provenance. FDA's approval of IMCIVREE rests on that program, and the underlying trials are registered and published. What does not exist: any published characterization of research-market or gray-market setmelanotide bulk material, any chain-of-custody data on it, and any impurity or stereochemical profiling of it. The inference rule stated on the citation index page is the same one used for the GLP-1 records and it is the point of the page: trial evidence generated on an approved finished product is not evidence about a different article whose disulfide connectivity, stereochemistry and counterion are all undeclared. One general finding underlies this catalog: Janvier and colleagues, J Pharm Biomed Anal 2018 (PMID 30165334), documents falsification and mislabeling of research-market peptides as an observed phenomenon rather than a theoretical one.

4 Storage & specification

Storage

Lyophilized powder, sealed and protected from moisture, stored at -80 degrees C, or at -20 degrees C for shorter holds; protected from light because of the tryptophan residue; and, as a disulfide-cyclized peptide, additionally protected from reducing conditions and from alkaline pH, at which disulfide scrambling is fastest. Supplier-stated handling for the research-grade material is -80 degrees C for up to 2 years or -20 degrees C for up to 1 year as a sealed powder, and, in solution, -80 degrees C for up to 6 months or -20 degrees C for up to 1 month. Those are vendor-stated conditions for a research reagent, not verified stability data on this company's own container-closure system, and they are labeled as such.

Shelf life

The retest interval is a conclusion from a stability study on this company's own defined container-closure system, and it is not inherited from the handling statement above, which is a supplier's handling note rather than stability data. The attributes that limit it are the ones panel P3 measures on this molecule: free thiol by Ellman assay together with the non-reducing against reducing chromatographic comparison for disulfide state, size-exclusion for disulfide-linked dimers and higher oligomers, tryptophan oxidation, and des-acetyl content from incomplete N-terminal capping. Lots rotate first-expiry-first-out on the date that study supports.