AOD9604: The hGH Fragment 176-191 Analog

AOD9604 is a synthetic 16-residue peptide, YLRIVQCRSVEGSCGF, with a molecular weight of 1815.1 g/mol and one internal disulfide bond. Its sequence corresponds to the C-terminal region of human growth hormone (hGH), residues 177 to 191, with a tyrosine in place of the phenylalanine at position 176. It is an investigational compound: it is not approved as a drug in the United States or elsewhere, FDA lists it among compounding nominations that were later withdrawn, and the World Anti-Doping Agency names it as a prohibited growth hormone fragment.

This profile covers the chemistry: identity, the disulfide ring, how the sequence relates to the parent hormone and to the closely related fragment hGH 176-191, what the originating laboratory reported, the regulatory record, and how the material behaves as a lyophilized reagent on the bench.

Identity at a glance

The values below come from the PubChem record for AOD9604 (CID 71300630).

Three structural points follow from that table. First, the molecule is not a simple linear chain: the Cys7–Cys14 bond closes an eight-residue ring, which is why the systematic name in PubChem describes a macrocycle. Second, the charge is modest, with two arginines (Arg3, Arg8) against one glutamate (Glu11), plus the free termini. Third, there is no methionine and no tryptophan, so the oxidation-prone residues that dominate storage planning for many peptides are absent here; the cysteines and the disulfide take their place as the reactive feature to protect. For the underlying chemistry of residues, termini and bonds, see what peptides are.

Relationship to human growth hormone

Human growth hormone is a 191-residue, four-helix-bundle protein with two disulfide bonds. The first, Cys53–Cys165, staples two distant parts of the chain together. The second, Cys182–Cys189, closes a small loop near the C-terminus. AOD9604 reproduces that small loop and the residues immediately around it, and keeps the disulfide.

One numbering trap is worth flagging, because it causes confusion when reading records rather than papers. The UniProt entry for somatotropin (P01241) is 217 residues long and includes a 26-residue signal sequence, so it lists the two disulfides at 79–191 and 208–215. Subtract 26 and they become the familiar 53–165 and 182–189 of the 191-residue mature hormone, the numbering used in the peptide literature and in the name hGH 176-191.

Two naming conventions circulate, and they describe closely related but distinct molecules:

The single substitution is the difference between the two entries, and it is why they have separate CAS numbers and separate masses. Tyrosine differs from phenylalanine by one hydroxyl group, 16 Da, and it gives the peptide a stronger absorbance near 280 nm, which is convenient for concentration measurement by UV. Both names appear in the literature and both are listed separately by anti-doping authorities.

A fragment of this size cannot fold like the parent protein. The four-helix bundle of hGH is built from the whole 191-residue chain, and its receptor-binding surfaces are formed by residues drawn from several helices at once. A 16-residue peptide carrying one small disulfide loop reproduces a piece of the sequence, not the folded architecture, and published work on the fragment has accordingly looked for activity that does not require the growth hormone receptor.

What the originating work reported

The primary sources are two papers from the Monash University group and their collaborators.

Ng and colleagues, writing in Hormone Research in 2000, described metabolic experiments with AOD9604 in obese Zucker rats, a strain carrying a leptin receptor mutation that is a standard model in metabolic biology. They reported increased lipolytic activity in adipose tissue from treated animals. They also reported that, in contrast with intact hGH, long-term exposure to the fragment did not change insulin sensitivity as measured by the euglycemic clamp technique. The paper is written as an early feasibility study, and its conclusions are framed as potential rather than demonstrated.

Heffernan and colleagues, in Endocrinology in 2001, addressed the receptor question directly using mice lacking the beta-3 adrenergic receptor (β3-AR), the adrenergic receptor subtype most associated with lipolysis in adipocytes. Both hGH and AOD9604 raised β3-AR messenger RNA levels in obese mice. In the knockout animals, the long-term changes seen in wild-type mice did not occur, but in an acute experiment the fragment still altered energy expenditure and fat oxidation measurements in animals without the receptor. The authors' conclusion was specific and worth quoting in substance: the lipolytic actions of hGH and of AOD9604 are not mediated directly through β3-AR, although both raise its expression.

That is the state of the mechanistic record in these sources. No binding partner for AOD9604 has been identified, no dissociation constant at a named receptor has been published in the work cited here, and the downstream signaling has not been mapped to a defined pathway. Later literature on the fragment exists, but the primary receptor question has not been resolved in the sources this profile relies on.

Research models

The models named in the two papers above are: obese Zucker rats; obese mice; β3-AR knockout mice and their wild-type controls; and adipose tissue taken from treated animals for lipolysis measurements. Both studies are rodent work from the same research program, published more than two decades ago. Independent replication in other laboratories is limited, and that limitation is part of an accurate description of the compound.

Regulatory and anti-doping status

AOD9604 is not an approved drug in the United States, and no marketing authorization elsewhere is documented in the sources cited here.

FDA compounding. FDA maintains a list of bulk drug substances that may present significant safety risks when used in compounding, with a separate table for substances that were nominated and then withdrawn by the nominator. AOD-9604 appears in that withdrawn table. FDA's stated concerns are immunogenicity for certain routes, complexities in peptide-related impurities and characterization of the active ingredient, and the limited safety-related information available, which the agency says leaves it unable to determine whether the substance would cause harm in people. FDA also notes serious adverse events that may be associated with it, while stating that causality is not clear.

Anti-doping. The 2026 World Anti-Doping Agency Prohibited List names AOD-9604 at S2.2.3, in the growth hormone subsection of S2, peptide hormones, growth factors, related substances and mimetics. The entry reads "growth hormone fragments, e.g. AOD-9604 and hGH 176-191", so both molecules in the table above are covered by name. S2 substances are prohibited at all times, in and out of competition.

Research supply. Material sold by Anhydrolabs is for in-vitro laboratory research only, and is not for human or veterinary diagnosis, treatment, or consumption.

Laboratory handling and storage

AOD9604 is supplied as a lyophilized powder in vacuum-sealed vials, available singly on the AOD9604 catalog page and in 10-vial kits. The disulfide governs most of the handling advice.

Keep the disulfide intact. Reducing agents break the Cys7–Cys14 bond and open the ring. Dithiothreitol, 2-mercaptoethanol and TCEP have no place in a buffer intended for the intact peptide, and reducing conditions in a cell assay medium should be considered when interpreting an experiment. A reduced species is 2 Da heavier than the cyclic form, which is easy to see by mass spectrometry.

Avoid alkaline solutions. Thiol-disulfide exchange accelerates above about pH 8, and with free thiols present it can produce dimers and scrambled species. Dissolving in water or a mildly acidic buffer, and keeping working solutions near neutral or slightly acidic pH, limits that chemistry. The general procedure is in how to reconstitute lyophilized peptides.

Dissolution. The hydrophobic N-terminal stretch can make the powder slow to dissolve at higher concentrations. Add solvent down the vial wall, let the cake wet through and swirl gently rather than vortexing, which shears and foams peptide solutions.

Storage. Keep the sealed powder frozen, dry and dark, and equilibrate the vial to room temperature before opening so moisture does not condense on the cake. In solution, aliquot for single use and freeze; repeated freeze-thaw is a common cause of degradation, as set out in how to store peptides and on the storage and handling page.

Identity checks. A certificate of analysis should show a mass consistent with 1815.1 g/mol for the cyclic form and purity reported as the area of the principal peak by reversed-phase HPLC. Because the tyrosine-for-phenylalanine substitution is a 16 Da difference, a mass 16 Da low is the signature of the native 176-191 fragment rather than AOD9604, and a mass 16 Da high can indicate oxidation elsewhere in the molecule. How those numbers are generated is covered in how HPLC measures peptide purity. Peptides with a free-thiol impurity profile deserve particular attention, since the same analysis that confirms mass will also reveal dimers.