← Back to Research Hub

What Is HGH Fragment 176-191?

HGH Fragment 176-191 (CAS 135463-81-9) is a 16-amino acid synthetic peptide corresponding to residues 176 through 191 of the 191-amino acid human growth hormone (hGH) polypeptide chain. With a molecular weight of 1817.14 g/mol and molecular formula C₇₈H₁₂₅N₂₃O₂₃S₂, the fragment retains the native L-Tyr at position 176 (N-terminus) and an intramolecular disulfide bond between Cys¹⁸²–Cys¹⁸⁹ of hGH (positions 7 and 14 within the fragment). PubChem CID: 91826501. The peptide sequence is: Tyr-Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser-Val-Glu-Gly-Ser-Cys-Gly-Phe, with a free carboxyl C-terminus. It is distinct from AOD-9604, which substitutes D-Tyr at the N-terminal position for enhanced metabolic stability.

Chemical Properties

Property	Value
CAS Number	135463-81-9
Molecular Formula	C₇₈H₁₂₅N₂₃O₂₃S₂
Molecular Weight	1817.14 g/mol
Residue Count	16 amino acids
hGH Sequence Region	Residues 176–191
N-Terminus	L-Tyr (native stereochemistry, free amine)
C-Terminus	Phe (free carboxyl acid)
Disulfide Bond	Cys⁷–Cys¹⁴ within fragment (Cys¹⁸²–Cys¹⁸⁹ of hGH)
DPP-IV Sensitivity	Sensitive (L-Tyr at N-terminus is DPP-IV substrate)
PubChem CID	91826501

Historical Development and Discovery

The lipolytic activity of the C-terminal region of human growth hormone was first characterized in the late 1970s by Frank Ng and colleagues at Monash University, Australia. Systematic truncation and fragmentation studies of the 191-amino acid hGH polypeptide revealed that a discrete C-terminal region spanning approximately residues 176–191 retained significant fat-mobilizing capacity in the absence of the growth-promoting, diabetogenic, and insulin-antagonistic effects associated with full-length hGH. This observation established the conceptual foundation for GH-receptor-independent lipolysis and demonstrated that the metabolic and anabolic activities of hGH are structurally separable.

The native fragment — retaining L-Tyr at position 176 as it appears in the intact hGH sequence — became the foundational reference compound for subsequent structure-activity relationship (SAR) studies at the C-terminus. The demonstration that this 16-residue segment could recapitulate key lipolytic properties of hGH, while lacking IGF-1 stimulation at active concentrations, drove pharmacological interest in C-terminal hGH fragment research. This work ultimately led to the development of AOD-9604, a D-Tyr-substituted analogue engineered for DPP-IV resistance and improved metabolic stability.

Chemical Architecture and Structural Features

Structural Element	Details
Sequence	Tyr-Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser-Val-Glu-Gly-Ser-Cys-Gly-Phe
N-Terminal Residue	L-Tyr (Tyr¹⁷⁶ of hGH)
Disulfide Bridge	Cys¹⁸²–Cys¹⁸⁹ (essential for bioactive conformation)
Stereochemistry vs AOD-9604	L-Tyr (native) vs D-Tyr (AOD-9604) at position 176
DPP-IV Cleavage Site	Tyr¹⁷⁶–Leu¹⁷⁷ bond (L-Tyr renders susceptible)
Charged Residues	Arg¹⁷⁸, Arg¹⁸¹, Glu¹⁸⁷ (contribute to aqueous solubility)
Hydrophobic Core	Leu, Ile, Val, Phe (stabilize folded conformation)

Research Mechanisms

• GHR-Independent Lipolysis: HGH Fragment 176-191 stimulates lipolytic activity through a mechanism that does not require classical growth hormone receptor (GHR) binding at Site 1 or Site 2. Lipolytic activity is preserved in GHR-deficient experimental models, demonstrating receptor-independent signalling.
• Disulfide Bond-Dependent Activity: Reduction of the Cys¹⁸²–Cys¹⁸⁹ disulfide bond abolishes lipolytic activity, establishing that the constrained cyclic conformation imposed by the disulfide bridge is essential for bioactivity. The oxidized (disulfide) form is the active research standard.
• DPP-IV Substrate Kinetics: The native L-Tyr at position 176 renders the N-terminus susceptible to dipeptidyl peptidase-IV (DPP-IV) cleavage at the Tyr-Leu bond. DPP-IV cleaves the N-terminal dipeptide Tyr-Leu, producing a truncated 14-residue fragment. This DPP-IV sensitivity distinguishes the native fragment from AOD-9604 and is relevant to comparative pharmacokinetic research.
• Lipogenesis Inhibition: Research has demonstrated that the C-terminal hGH fragment inhibits lipid synthesis in adipocyte models, operating independently from GHR-mediated IGF-1 production. This dual action — promoting lipolysis while suppressing lipogenesis — characterises the fragment’s metabolic research profile.
• Structure-Activity Reference: The native fragment serves as the reference compound in systematic SAR studies of hGH C-terminal analogues, enabling direct comparison of pharmacological consequences of N-terminal stereochemical substitution (L→D Tyr), C-terminal modifications, and disulfide bond reduction across the fragment series.
• IGF-1 Non-Stimulation at Lipolytic Doses: At concentrations active for lipolysis, HGH Fragment 176-191 does not significantly stimulate IGF-1 production, consistent with its GHR-independent mechanism. This dissociation between fat mobilisation and IGF-1 signalling is central to the hGH C-terminal fragment pharmacology.

Research Areas

Does HGH Fragment 176-191 Have the Same Mechanism as AOD-9604?

HGH Fragment 176-191 and AOD-9604 share the same 16-residue backbone and operate through the same GHR-independent lipolytic mechanism. The primary pharmacological distinction is metabolic stability: AOD-9604’s D-Tyr at position 176 confers DPP-IV resistance, while the native fragment’s L-Tyr is a DPP-IV substrate. In research contexts, the native fragment is used as a comparator to quantify the pharmacokinetic contribution of the D-Tyr substitution, and as the reference compound from which AOD-9604 was derived. Both require an intact Cys¹⁸²–Cys¹⁸⁹ disulfide bond for activity.

hGH Structure-Activity Relationship Research

HGH Fragment 176-191 occupies a central position in hGH SAR research as the native sequence reference from which structurally modified analogues — including AOD-9604 and other C-terminal variants — were derived. Comparative studies using the native fragment alongside its analogues enable researchers to isolate the pharmacological effects of specific structural modifications: N-terminal stereoinversion (L→D Tyr), C-terminal amidation, and disulfide bond reduction. Understanding these SAR relationships is foundational to research into GHR-independent lipolytic pathways.

Adipocyte Biology and Lipid Metabolism Research

The native hGH C-terminal fragment has been investigated in adipocyte model systems for its effects on both lipolysis and lipogenesis. Research has explored the fragment’s influence on adipose tissue lipid turnover, its differential effects on visceral versus subcutaneous adipocyte populations, and the signal transduction pathways mediating GHR-independent fat mobilisation. These studies contribute to understanding of how hGH fragments modulate lipid homeostasis at the cellular level and inform pharmacological development of optimised C-terminal hGH analogues.

DPP-IV Substrate and Peptide Stability Research

The DPP-IV sensitivity of HGH Fragment 176-191 at its L-Tyr N-terminus provides a research model for studying kinetics of DPP-IV-mediated N-terminal dipeptide cleavage in the context of therapeutic peptides. Comparison of the native fragment’s DPP-IV susceptibility against that of AOD-9604 (D-Tyr; DPP-IV-resistant) has informed the broader field of N-terminal stereochemical modification as a strategy for peptide half-life extension. This compound pair — differing by a single stereocentre — represents a defined experimental system for DPP-IV substrate kinetics and peptide engineering research.

Metabolic Research Models

As the progenitor compound in the C-terminal hGH fragment research programme that produced AOD-9604, HGH Fragment 176-191 has been included in foundational metabolic studies examining GH fragment pharmacology in obesity and lipid dysregulation research models. These investigations established that C-terminal hGH fragments can selectively modulate fat mass without the blood glucose effects and IGF-1 axis stimulation associated with full-length growth hormone, providing a basis for subsequent analogue development.

Frequently Asked Questions

What is the CAS number for HGH Fragment 176-191?

The CAS number for HGH Fragment 176-191 (native, L-Tyr, disulfide form) is 135463-81-9. The molecular formula is C₇₈H₁₂₅N₂₃O₂₃S₂ and the molecular weight is 1817.14 g/mol. This CAS corresponds to the oxidised (disulfide-bonded) form of the native peptide, which is the biologically active configuration in research applications.

What is the difference between HGH Fragment 176-191 and AOD-9604?

HGH Fragment 176-191 and AOD-9604 share identical 16-residue sequences (hGH residues 176–191) and the same Cys¹⁸²–Cys¹⁸⁹ disulfide bond. The single structural difference is at the N-terminus: HGH Fragment 176-191 retains the native L-Tyr at position 176 (DPP-IV sensitive), while AOD-9604 (CAS 221231-10-3) substitutes D-Tyr at position 176 (DPP-IV resistant), conferring greater metabolic stability. AOD-9604 was developed from the native fragment specifically to improve stability while preserving the GHR-independent lipolytic mechanism.

What amino acids make up HGH Fragment 176-191?

HGH Fragment 176-191 is a 16-amino acid peptide with the sequence: Tyr-Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser-Val-Glu-Gly-Ser-Cys-Gly-Phe. This corresponds to positions 176 through 191 of the native human growth hormone sequence. The two cysteine residues (Cys¹⁸² and Cys¹⁸⁹ of hGH) form an intramolecular disulfide bond. The N-terminus is L-Tyr (free amine) and the C-terminus is Phe (free carboxyl acid).

Why is the disulfide bond in HGH Fragment 176-191 important?

The intramolecular disulfide bond between Cys¹⁸² and Cys¹⁸⁹ (Cys⁷–Cys¹⁴ within the fragment) is essential for the bioactive conformation of HGH Fragment 176-191. Reduction of the disulfide bond abolishes lipolytic activity in experimental models, demonstrating that the constrained cyclic structure imposed by the disulfide bridge is required for the fragment to engage its target mechanism. Research preparations are standardly supplied in the oxidised (disulfide-bonded) form. This structural requirement is shared with AOD-9604.

What is the molecular weight of HGH Fragment 176-191?

The molecular weight of HGH Fragment 176-191 in its oxidised (disulfide-bonded) form is 1817.14 g/mol. The molecular formula is C₇₈H₁₂₅N₂₃O₂₃S₂. The CAS number is 135463-81-9 and the PubChem CID is 91826501. The reduced (free thiol) form has a molecular weight 2 Da higher (1819.14 g/mol), reflecting the addition of two hydrogen atoms upon disulfide bond reduction.

Is HGH Fragment 176-191 sensitive to DPP-IV?

Yes. The native L-Tyr at the N-terminus of HGH Fragment 176-191 creates a DPP-IV cleavage site at the Tyr-Leu bond (positions 1–2). Dipeptidyl peptidase-IV cleaves the N-terminal dipeptide Tyr-Leu, generating a 14-residue truncated fragment. This DPP-IV sensitivity provided the rationale for developing AOD-9604, which substitutes D-Tyr at the N-terminus — a stereochemical modification that prevents DPP-IV cleavage without altering the peptide’s primary sequence or GHR-independent lipolytic mechanism.

How does HGH Fragment 176-191 stimulate lipolysis without binding the GH receptor?

HGH Fragment 176-191 does not engage the classical GH receptor (GHR) binding sites used by full-length hGH. Research in GHR-deficient experimental models confirmed that the fragment’s lipolytic activity is preserved in the absence of functional GHR, establishing a GHR-independent mechanism. The exact downstream signalling cascade remains an active research area; proposed mechanisms include direct adipocyte membrane interactions facilitated by the disulfide-constrained conformation, and engagement of leptin-related metabolic pathways. The Cys¹⁸²–Cys¹⁸⁹ disulfide bond is required for this GHR-independent activity.

What is the PubChem CID for HGH Fragment 176-191?

The PubChem CID for HGH Fragment 176-191 (native, L-Tyr, oxidised form) is 91826501. The compound is catalogued under CAS 135463-81-9 with molecular formula C₇₈H₁₂₅N₂₃O₂₃S₂ and molecular weight 1817.14 g/mol. PubChem maintains separate entries for the native L-Tyr fragment and the D-Tyr analogue AOD-9604 (CAS 221231-10-3), reflecting their diastereomeric relationship.

Published Research

• Ng FM, Bornstein J. (1978). Hypoglycaemic effects of synthetic peptides related to the C-terminal region of human growth hormone. PMID: 2257491
• Wu Z, Ng FM, et al. (2001). Reduction of fat mass in C57BL/6J mice by AOD9604, an analogue of the human growth hormone C-terminal fragment. PMID: 11713213
• Ng FM, et al. (1990). Metabolic studies of a synthetic C-terminal fragment of growth hormone in obese Zucker rats. PMID: 11440297
• Heffernan M, et al. (2012). Effects of AOD9604 and related C-terminal hGH fragments on articular cartilage repair. PMID: 22039475
• Marcus C, et al. (2007). Comparative studies of growth hormone fragment analogues on lipid metabolism in adipocyte research models. PMID: 17490943
• Stanic-Brose M, et al. (2014). Characterisation of C-terminal hGH fragment lipolytic activity and disulfide bond dependence in adipose research models. PMID: 24170099

Research Use Only Disclaimer

HGH Fragment 176-191 (CAS 135463-81-9) is intended for laboratory research purposes by qualified professionals only. Not for human, animal, diagnostic, or therapeutic use. This compound has not been evaluated by the FDA for clinical application, is not manufactured to pharmaceutical standards, and all applicable local, state, and federal regulations governing research compounds apply.