Tesamorelin is composed of 44 amino acid sequences of human growth hormone releasing factor (GRF). 3-hexenoyl is attached to the N-terminal residue of its tyrosine. The molecular formula is C221H366N72O67S. XC2H4O (x ≈ 7), CAS 901758-09-6 and CAS 218949-48-5, with a relative molecular weight (free base) of 5135.9. Analogues are a new growth hormone releasing factor that can not only restore normal secretion of growth hormone in the body, but also reduce the increase in visceral adipose tissue (VAT), improve blood lipid abnormalities and quality of life, and maintain the dynamic balance of glucose in the body. The drug was approved by the US Food and Drug Administration in November 2010 for the treatment of HIV related fat metabolism disorder syndrome. We have tesamorelin peptide for sale, but it should be noted that the products provided by Shaanxi BLOOM Tech Co., Ltd. are for laboratory use only.
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Tesamorelin COA
A method for purification by reversed phase high performance liquid chromatography includes the following steps:
1) The timorelin rough skin obtained from solid phase synthesis is dissolved in deionized water, and the stationary phase is a reversed-phase silica gel column with tetraalkyl silane bonded silica gel, octaalkyl silane bonded silica gel or octadecyl bonded silica gel, and the mobile phase is two phases, wherein the triethylamine phosphate buffer solution is phase A, and the chromatogram pure acetonitrile is phase B, and gradient elution purification is performed to collect the skin solution of the target peak
2) The obtained solution is concentrated by vacuum rotary evaporation, and the concentrated solution is reserved for standby
3) Use anion exchange resin to exchange and convert into coolate
4) The final high-purity cortisone solution is concentrated and freeze-dried by decompressing, rotating and evaporating again to obtain a powdery finished product.
This method is suitable for industrial purification of temorelin. It can not only obtain refined skin with purity greater than 98.0%, but also produce in batches to meet the requirements of high purity, high yield, low cost and high efficiency.
Synthesis method
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The peptide resin A was prepared by successively coupling Fmoc-Leu-OH and other protective amino acids with a resin as carrier in the order of temorelin
The full protective fragment B1-Bn (n is an integer satisfying 2 ≤ n<21) was synthesized by solid phase synthesis method respectively. The sequence of the fragments is part of the sequence of temorelin, and the sequence of total amino acids after connecting A and B1-Bn is the same as that of temorelin
The peptide resin A was successively coupled with the full-protective fragment B1-Bn and trans-hexaenoic acid on the solid phase to obtain the temorelin peptide resin
Pyrolysis of temorelin peptide resin to obtain crude peptide. The method for preparing temorellin is easy to operate, low in cost, simple in purification and high in yield
The research history focuses on the treatment of fat metabolism disorders associated with HIV (Human Immunodeficiency Virus). Below are some key points about the research history:
1. Preliminary Findings
In the HIV-infected patient population, some medications may cause impaired fat metabolism during treatment, especially excessive accumulation of abdominal fat. This change not only affects the physical appearance of patients, but is also associated with an increased risk of metabolic abnormalities and cardiovascular disease. Therefore, the search for drugs that can effectively treat this fat metabolism disorder has become an important direction of research.
2. Mechanism of action study
Regulating the release of growth hormone (GH) in the body by mimicking and enhancing the action of human growth hormone releasing hormone (GHRH). Growth hormone plays a key role in the regulation of growth, synthesis and metabolism of body tissues, and it stimulates the secretion of growth hormone by binding to the GHRH receptor in the pituitary gland, thereby increasing the level of GH in the body. This discovery provides a theoretical basis for the treatment of HIV-associated lipid metabolism disorders with Tesamorelin.
3. Clinical studies
Based on the mechanism of action, researchers have conducted several clinical trials to evaluate its efficacy in treating HIV-associated dyslipidemia. These studies have shown that treatment significantly reduces the accumulation of abdominal fat and is also effective in improving patients' symptoms of fat loss. This can have a positive impact on both the psychological and physical health of patients.
4. FDA Approval
Based on the positive results of these clinical studies, it (Tesamorelin acetate salt, trade name Egrifta) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV-associated disorders of fat metabolism in 2010. This was the first drug approved by the FDA for the treatment of lipid metabolism disorders.
In summary, the history of Tesamorelin research has been one of discovery of potential therapeutic effects, in-depth exploration of mechanisms of action, validation of efficacy through clinical trials, and ultimately regulatory approval. The success of this process not only provides a new therapeutic option for HIV-infected patients, but also offers new ideas for the treatment of other disorders associated with disorders of fat metabolism.
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Tesamorelin inhibits GSK-3 β and reduces tau protein phosphorylation through IGF-1
Tesamorelin is an artificially synthesized growth hormone releasing factor (GHRH) analog that can stimulate the secretion of growth hormone (GH) from the anterior pituitary gland, thereby affecting the level of insulin-like growth factor-1 (IGF-1). In recent years, research has found that Tesamorelin may regulate tau protein phosphorylation through IGF-1-related signaling pathways, bringing new hope for the treatment of neurodegenerative diseases.
The characteristics of GSK-3 β and its relationship with tau protein phosphorylation
Structure and Enzymatic Characteristics of GSK-3 β
Glycogen synthase kinase-3 β (GSK-3 β) is a serine/threonine protein kinase that is widely present in cells. GSK-3 β has unique structural characteristics and its activity is regulated by multiple factors. At rest, GSK-3 β has a certain basal activity, and its activity is further enhanced when activated by upstream signals. GSK-3 β has a wide range of substrates and can phosphorylate various proteins, participating in various signaling pathways and physiological processes within cells.
Phosphorylation of tau protein by GSK-3 β
Tau protein is a microtubule associated protein that mainly participates in the assembly and stability of microtubules in neurons. There are multiple phosphorylation sites on tau protein, and GSK-3 β is one of the main kinases that catalyze tau protein phosphorylation. GSK-3 β can specifically recognize and phosphorylate specific serine and threonine residues of tau protein, such as Ser396, Thr231, etc. The excessive phosphorylation of tau protein can lead to a decrease in its binding ability to microtubules, disruption of microtubule structure, which in turn affects the material transport and normal function of neurons, ultimately leading to neuronal death.
The role of GSK-3 β in neurodegenerative diseases
In neurodegenerative diseases such as AD, the activity of GSK-3 β is abnormally increased, which is closely related to the excessive phosphorylation of tau protein and the formation of neurofibrillary tangles. Research has shown that inhibiting the activity of GSK-3 β can reduce the phosphorylation level of tau protein, improve neuronal pathological changes, and delay disease progression. Therefore, GSK-3 β has become one of the important targets for the treatment of neurodegenerative diseases.
The mechanism of Tesamorelin stimulating IGF-1 secretion
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Interaction between Tesamorelin and GHRH receptor
Tesamorelin, as a GHRH analog, can specifically bind to GHRH receptors on the surface of anterior pituitary cells. This binding has high affinity and specificity, similar to the interaction between natural GHRH and receptors. When Tesamorelin binds to the GHRH receptor, it causes a conformational change in the receptor, activating the G protein coupled signaling pathway within the cell.
Activation of intracellular signaling pathways
After Tesamorelin binds to GHRH receptors, the activated G protein further activates adenylate cyclase (AC), leading to an increase in intracellular cyclic adenosine monophosphate (cAMP) levels. CAMP, as a second messenger, activates protein kinase A (PKA). PKA can phosphorylate various downstream target proteins, including transcription factors, thereby promoting the transcription and expression of GH genes, ultimately leading to an increase in GH secretion.
Induction of IGF-1 synthesis by GH
GH secreted into the bloodstream acts on tissues such as the liver, activating the JAK-STAT signaling pathway within liver cells to promote transcription and expression of the IGF-1 gene. After binding to GH receptors on the surface of liver cells, GH activates receptor related JAK kinases, which further phosphorylate STAT proteins. Phosphorylated STAT proteins form dimers, enter the nucleus, bind to the promoter region of the IGF-1 gene, and initiate the synthesis and secretion of IGF-1.
IGF-1 inhibits the signaling pathway of GSK-3 β activity
Activation of IGF-1 receptor
After IGF-1 is secreted into the bloodstream, it binds to the IGF-1 receptor (IGF-1R) on the surface of target cells. IGF-1R is a tyrosine kinase receptor. When IGF-1 binds to the receptor, it causes a conformational change and activates the receptor's tyrosine kinase activity. Activated IGF-1R self phosphorylates and phosphorylates downstream signaling molecules, such as insulin receptor substrate (IRS) proteins.
Activation of PI3K Akt signaling pathway
Phosphorylated IRS proteins can recruit and activate phosphatidylinositol 3-kinase (PI3K). PI3K catalyzes the formation of phosphatidylinositol-3,4,5-triphosphate (PIP3) from phosphatidylinositol-4,5-diphosphate (PIP2) on the cell membrane. PIP3, as a second messenger, can recruit protein kinase B (Akt) onto the cell membrane and activate it. Activated Akt is a key molecule that inhibits GSK-3 β activity.
Akt's inhibitory effect on GSK-3 β
Akt can directly phosphorylate specific serine residues (such as Ser9) of GSK-3 β, and the activity of phosphorylated GSK-3 β is inhibited. This inhibitory effect prevents GSK-3 β from phosphorylating substrates such as tau protein, thereby reducing abnormal phosphorylation levels of tau protein.
The effect of GSK-3 β activity inhibition on tau protein phosphorylation levels
In vitro experimental research
In vitro cell experiments, researchers exposed neuronal cells to the Tesamorelin or IGF-1 environment and then measured the phosphorylation level of tau protein. The results showed that after treatment with Tesamorelin and IGF-1, the activity of GSK-3 β in neuronal cells was significantly reduced, and the phosphorylation levels of tau protein at multiple phosphorylation sites were also significantly decreased. This indicates that Tesamorelin inhibits GSK-3 β activity through the IGF-1-Akt signaling pathway, effectively reducing tau protein phosphorylation.
Animal experimental research
In animal models, such as transgenic AD mouse models, after treatment with Tesamorelin, the levels of IGF-1 in mouse brain tissue increased, GSK-3 β activity was inhibited, and tau protein phosphorylation levels decreased. At the same time, the cognitive function of mice was improved and neuronal damage was reduced. These animal experimental results further confirm the effectiveness of Tesamorelin's mechanism of inhibiting GSK-3 β and reducing tau protein phosphorylation through IGF-1 in vivo.
FAQ
1. Question: Does Tesamorelin have potential applications for non-HIV-related visceral fat accumulation? What are the current data?
Answer: Although Tesamorelin is currently only approved by the FDA for the treatment of visceral fat accumulation related to HIV, there have been small-scale studies exploring its effects in other causes of visceral obesity (such as metabolic syndrome, non-alcoholic fatty liver disease). Preliminary data suggest that it may also reduce visceral fat and improve insulin sensitivity, but the long-term efficacy and safety have not been recognized by authoritative institutions. It is worth noting that its mechanism of action (a growth hormone-releasing hormone analogue) theoretically applies to any cause of excessive visceral fat accumulation, but this is considered "off-label use" and the treatment cost is extremely high (up to over $30,000 per year), which limits the expansion of related research.
2. Q: Are there any specific requirements for the injection site of Tesamorelin? Why is abdominal injection recommended in clinical practice?
A: The clinical recommendation is to inject under the skin of the abdomen (avoiding a 5-centimeter area around the navel), and this is not a random choice. Early pharmacokinetic studies found that compared to injection in the thigh or arm, the absorption of the drug is more stable and the incidence of local adverse reactions (such as redness, swelling, and hardening) is slightly lower. This may be related to the blood supply and tissue density characteristics of the subcutaneous fat in the abdomen. In addition, the injection site needs to be rotated to avoid fat malnutrition (atrophy or hyperplasia), which is particularly important for HIV patients with abnormal fat distribution.
3. Q: Will long-term use of Tesamorelin affect the secretion rhythm of one's own growth hormone (GH) or lead to feedback inhibition?
A: There is a theoretical risk, but the existing clinical data (with the longest study lasting approximately 2 years) do not show that Tesamorelin causes definite GH axis feedback inhibition or permanent secretion disorder. As a growth hormone-releasing hormone (GHRH) analogue, it mimics physiological pulse stimulation and is more likely to maintain the rhythmicity of GH secretion compared to direct exogenous growth hormone supplementation. However, after discontinuation, visceral fat usually returns to the pre-treatment level within several months, suggesting that its effect is "reversible regulation" rather than a cure. The long-term impact on the hypothalamic-pituitary axis has not been sufficiently studied in the population using it for ultra-long-term use (>5 years).
4. Question: What are the specific challenges in the synthesis of Tesamorelin and the purity of the polypeptide? Why is the development of generic drugs more difficult?
Answer: Tesamorelin is a synthetic peptide consisting of 44 amino acids. Its production encounters two rare difficulties:
Stability issue: The peptide chain is prone to oxidation or hydrolysis, especially the tyrosine at the 1st position and the amide C-terminal at the 44th position. This requires extremely strict conditions for production processes (such as solid-phase synthesis, purification, and freeze-drying).
Immunogenicity risk: Even minor sequence errors or impurities (such as truncated peptides) can trigger the production of antibodies, potentially neutralizing endogenous GHRH or reducing efficacy. The original drug controls impurity content to <0.1% through proprietary purification technology, while generic drugs need to prove bioequivalence not only in terms of pharmacokinetics but also in terms of immunogenicity characteristics, which increases the development barrier.
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