Tesamorelin
[CAS# 218949-48-5]

Identification

• Classification: Biochemical >> Peptide
• Name: Tesamorelin
• Synonyms: N-[(3E)-1-Oxo-3-hexen-1-yl]-somatoliberin (human pancreatic islet); TH 9507
• Protein Sequence: YADAIFTNSYRKVLGQLSARKLLQDIMSRQQGESNQERGARARL
• Molecular Formula: C₂₂₁H₃₆₆N₇₂O₆₇S
• Molecular Weight: 5135.78
• CAS Registry Number: 218949-48-5 (804475-66-9)
• SMILES: CC/C=C/CC(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC2=CC=CC=C2)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)NCC(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCNC(=N)N)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CC(C)C)C(=O)N

Discovory and Applicatios

Tesamorelin is a synthetic analogue of human growth hormone-releasing factor (GRF or GHRH), developed to stimulate the production and release of endogenous growth hormone (GH) in a regulated physiological manner. It is a 44-amino acid peptide that incorporates a structural modification at the N-terminal end to improve stability against enzymatic degradation, thus enhancing its pharmacokinetic properties. This compound was engineered to maintain the biological activity of native GRF while extending its half-life in circulation. The development of tesamorelin can be traced back to the search for effective agents that could address hormone deficiencies and related metabolic conditions through endogenous hormone regulation, rather than direct hormone replacement.

Tesamorelin was developed and commercialized by Theratechnologies Inc., a biopharmaceutical company based in Canada. It underwent extensive preclinical and clinical evaluations to assess its efficacy in stimulating GH secretion and its downstream physiological effects. Tesamorelin binds to and activates the GHRH receptor in the anterior pituitary, promoting the release of growth hormone and consequently increasing levels of insulin-like growth factor-1 (IGF-1), a key mediator of GH action in peripheral tissues. This mechanism makes tesamorelin effective for conditions associated with reduced GH activity.

The most well-documented and clinically approved use of tesamorelin is in the treatment of HIV-associated lipodystrophy, particularly for reducing excess abdominal visceral adipose tissue (VAT). Lipodystrophy is a common complication in HIV-infected individuals undergoing antiretroviral therapy, characterized by abnormal fat distribution and metabolic disturbances. Tesamorelin was approved by the U.S. Food and Drug Administration (FDA) in 2010 for this indication under the trade name Egrifta. Clinical studies demonstrated that tesamorelin significantly reduces visceral fat accumulation without adversely affecting subcutaneous fat or glucose metabolism in most patients. These effects were reversible upon discontinuation of treatment, highlighting the need for sustained administration to maintain therapeutic benefits.

The approval of tesamorelin marked a significant advancement in the treatment of HIV-related metabolic complications. Prior to its introduction, therapeutic options for managing lipodystrophy were limited and often ineffective. Tesamorelin offered a targeted approach by harnessing the body's own hormonal pathways, improving not only fat distribution but also potentially enhancing the quality of life for affected individuals. Patients receiving tesamorelin showed improvements in VAT, triglyceride levels, and certain markers of cardiovascular risk, though the long-term effects on clinical outcomes such as cardiovascular events remain under investigation.

Beyond its approved use, tesamorelin has also been studied in other settings where GH modulation might offer therapeutic value. For instance, research has examined its effects on liver fat content in patients with nonalcoholic fatty liver disease (NAFLD), particularly in those co-infected with HIV. These exploratory studies suggest that tesamorelin may reduce hepatic steatosis and improve liver enzyme profiles in this population. However, such applications are still being evaluated and have not been formally approved for clinical use.

Tesamorelin's molecular characteristics, including its resistance to degradation and specific receptor targeting, make it a valuable model for peptide drug design. It represents one of the few successful cases of a peptide hormone-releasing factor analogue achieving clinical application, highlighting the potential of rational peptide engineering in modern therapeutics.

The safety profile of tesamorelin has been established through clinical trials and post-marketing surveillance. Common side effects include injection site reactions, peripheral edema, and muscle pain. Tesamorelin is contraindicated in individuals with active malignancy due to its GH-stimulating activity, which may promote tumor growth. Additionally, it is not recommended for use in pregnant women or individuals with a history of hypersensitivity to the compound or its components.

In summary, tesamorelin is a synthetic GHRH analogue developed for therapeutic use in conditions of GH dysregulation. Its primary clinical application is in the management of HIV-associated lipodystrophy, where it provides a targeted and physiological method for reducing visceral fat. Tesamorelin’s discovery and approval have contributed significantly to the field of metabolic medicine and peptide therapeutics, establishing a foundation for further research into hormone-regulating compounds.

References

2018. Peptide Pharmaceuticals: Opportunities, Prospects, and Limitations. Molecular Genetics, Microbiology and Virology, 33(1).
DOI: 10.3103/s0891416818010123

2023. Strategies to improve the physicochemical properties of peptide-based drugs. Pharmaceutical Research, 40(3).
DOI: 10.1007/s11095-023-03486-0

2024. Growth hormone-releasing hormone and its analogues in health and disease. Nature Reviews. Endocrinology, 20(12).
DOI: 10.1038/s41574-024-01052-1