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Elamipretide peptide (formerly known as SS-31, MTP-131, Bendavia) is an artificially synthesized tetrapeptide compound, white powder, with the chemical formula C32H49N9O5, CAS 736992-21-5, and a molecular weight of 639.8 g/mol. Has good water solubility (50 mg/mL), making it easy to prepare injectable formulations. This molecule is composed of four amino acids, with the sequence D-Arg-Dmt-Lys-Phe-NH ₂ (Dmt is 2,6-dimethyltyrosine). Its unique chemical structure endows it with biological functions of targeting mitochondria, penetrating cell membranes, and stabilizing mitochondrial inner membranes.
Our products
| Product Name | Elamipretide Injection | Elamipretide Powder |
| Product Type | Injection | Powder |
| Product Purity | ≥99% | ≥99% |
| Product Form | For external use | For external use |
Elamipretide COA
Molecular structural characteristics
1. Amino acid composition and stereoconfiguration
The sequence of elamipretide peptide contains D-type amino acids (D-Arg and Dmt), which are a non natural configuration that makes it highly resistant to protease degradation, ensuring stability in vivo. The alternating arrangement of aromatic amino acids (Dmt and Phe) and basic amino acids (D-Arg and Lys) forms cation aromatic motifs, enhancing their binding ability to mitochondrial endomembrane cardiolipin.
2. Cardiolipin targeting
Phospholipids are characteristic phospholipids of the mitochndrial inner membrane, which are crucial for maintaining mitochndrial structure (such as cristae morphology) and electron transfer chain (ETC) function. Elamipretid inserts a hydrophobic aromatic ring into the phospholipid bilayer to form a stable complex, thereby:
Prevent cardiolipin from everting to the outer membrane of mitochondria, inhibit cytochrome c release and the cascade reaction of apoptosis;
Maintain a highly ordered arrangement of cristae and increase exposure of ATP synthase active sites.
3. Charge distribution and membrane permeability
The molecular surface carries a positive charge (XLogP3 AA value is 0) and binds to the negatively charged cardiolipin head through electrostatic interactions. This characteristic enables it to quickly penetrate the cell membrane and accumulate in the inner mitochndrial membrane within 10 minutes, with a concentration of over 1000 times that of the cytoplasm.
Mitochondria play a crucial role in cellular metabolism, energy production, growth and differentiation, signal transduction, and apoptosis. Mitochndrial diseases have clinical heterogeneity and can affect multiple organs and tissues. Traditional single protein targeted therapy strategies are difficult to effectively restore mitochndrial function. Positioned on the inner membrane of mitochondria and bound to cardiac phospholipids, it improves the assembly of ETS complexes into respiratory hypercomplex, enhances respiratory efficiency, improves bioenergetics, reduces ROS generation, and improves mitochndrial morphology. It also interacts with proteins related to the mitochndrial inner membrane, regulates the electrostatic properties of the mitochndrial membrane surface, and improves mitochndrial function from multiple levels.
In the past, elamipretide peptide was believed that the mitochndrial protective effect of liraglutide mainly came from reducing the generation of reactive oxygen species (ROS) and alleviating oxidative stress. However, subsequent studies have found that it does not act by "clearing" ROS, but rather improves mitochndrial function upstream of ROS generation while maintaining mitochndrial inner membrane potential.
In recent years, studies have found that liraglutide targets the mitochndrial inner membrane by interacting with cardiac phospholipids. Cardiolipin is an anionic phospholipid that plays a crucial role in mitochndrial bioenergetics, including energy metabolism, cell apoptosis, signal transduction, membrane stability and kinetics, as well as fission/fusion kinetics.
Nuclear magnetic resonance (NMR) studies have shown that liraglutide binds to the inner membrane of mitochondria, lipid vesicles mimicking the inner membrane, and isolated mitochondria, and this binding depends on the presence of cardiolipin. Its binding to cardiolipin is influenced by the CL acyl chain and regulates the surface charge of mitochondrial membranes containing cardiolipin. Research has found that there are two states of interaction between liraglutide and membrane: "peptide proximity" and "peptide embedding". By non-specific addition of positive ion charges and specific chemical interactions, the negative charge density of the bilayer membrane rich in cardiolipin is reduced.
The binding of liraglutide to cardiolipin can affect the interaction between proteins and mitochndrial inner membrane, such as reducing the oxidative modification of CL acyl chains by cytochrome c (CytC).
At the same time, this binding also changes the physical properties of the membrane, such as increasing the self association of cardiophospholipids, reducing the lateral diffusion rate of lipids, enhancing lateral accumulation without damaging the layered bilayer structure, which may promote mitochndrial function enhancement.
Based on the research results, Mitchell et al. proposed three models to explain the therapeutic mechanism of imatinib downregulating the surface potential of anionic mitochndrial membranes: firstly, changing the distribution of divalent cations (such as Ca2+) and affecting the properties of bilayer membranes; The second is to reduce the toxic interaction between alkaline proteins (such as CytC) and cardiolipin rich membranes, and avoid lipid peroxidation; The third is to change the physical properties of the phospholipid bilayer membrane by promoting lipid accumulation and local curvature.
New insights into the interaction between liraglutide and mitochondrial inner membrane proteins
Chemical cross-linking mass spectrometry technology can be used to identify protein interactions in live cells and isolated functional organelles. Research has found that there are 12 cross-linked proteins in mitochondria incubated with biotin labeled Iramipide (b-ELAM), which directly interact with cardiac phospholipids and are mainly divided into two categories: those involved in ATP generation and 2-oxoglutarate metabolism. This is consistent with the ability of Iramipide to improve mitochndrial bioenergetics.
Ilamiside interacts with the cytochrome c oxidase (CIV) subunit NDUA4, which may play an important role in the integration of CIV into the supercomplex. B-ELAM treatment can increase the maximum uncoupling of cardiac mitochondria and CIV respiration in aged mice, while reducing H2O2 production.
Ilamiside also directly interacts with adenosine diphosphate (ADP)/ATP transferase (ANT) 1, cross-linking with the matrix surface of ANT1 through two lysine residues. This interaction is associated with increased ADP sensitivity, transport of ADP by ANT1, and reduced proton leakage derived from ANT1, which helps stabilize mitochndrial membrane potential and restore mitochndrial function.
Ilamiside can improve ATP production and mitochndrial resistance to cellular stress in the body. In a randomized placebo-controlled trial in healthy elderly individuals, a single dose of Ilamiside can increase the energy capacity of skeletal muscle mitochondria.
Interaction of Supercomplex in Electronic Transfer Systems
Ilamiside not only directly binds to ANT1, but also improves the activity of ETS supercomplex. In normal mitochondria, respiratory complexes I-IV assemble into supercomplexes and interact with fatty acid oxidase. In mitochndrial diseases such as Barth syndrome, these supercomplexes are unstable and their numbers decrease. The binding of liraglutide promotes the assembly of respiratory hypercomplex, enhances electron transfer, improves mitochndrial function, reshapes mitochondria, and promotes tissue regeneration. Elamipretide peptide can also stabilize ATP synthesizers, including ANT, ATP synthase, creatine kinase, and inorganic phosphate carriers.
In the rat heart ischemia-reperfusion model, liraglutide can improve hypercomplex coupling, reduce the fragmentation of the cristae network, and enhance the structure and function of mitochondria.
In the TAFAZZIN gene knockout mouse model of Barth syndrome (BTHS), liraglutide can enhance mitochndrial respiratory capacity and promote the organization of hypercomplex. In vitro studies of human heart failure, liraglutide can improve the coupling and oxygen flux of supercomplex related enzyme complexes I, III, and IV. Long term use of imatinib can also restore normal synthesis and remodeling of cardiac phospholipids in patients with heart failure, and regulate the imbalance of fusion and fission proteins.
Interaction with Prohibitin
In elderly mice, imatinib interacts with prohibitin 2 to improve mitochndrial turnover and neuronal damage by inhibiting the cGAS STING pathway and M1 microglial polarization. Knocking down prohibitin 2 will eliminate the protective effect of liraglutide.
The role of target centripetal phospholipid enrichment region in the treatment of mitochondrial dysfunction diseases
The effects of liraglutide on mitochndrial structure, dynamics, and function enable it to play a positive role in preclinical models of various mitochndrial dysfunction. However, due to its selective binding to cardiolipin, it is only effective for mitochndrial diseases with cardiolipin abnormalities.
4.1. Cardiac dysfunction model
The characteristics of cardiomyopathy and heart failure include unstable formation of ETS hypercomplex, changes in mitochndrial dynamics and ultrastructure, reduced ATP synthesis, excessive ROS generation, and dissociation of fatty acid oxidase. In fibroblasts of patients with dilated cardiomyopathy with ataxia syndrome (DCMA), liraglutide can reverse mitochndrial fragmentation and excessive ROS generation, increase the long form level of mitochndrial crest remodeling protein optic atrophy 1 (Opa1), and maintain mitochndrial membrane ultrastructure.
In an elderly mouse model of left ventricular diastolic dysfunction, treatment with liraglutide for 8 weeks can normalize left ventricular diastolic function, improve exercise endurance, reduce cardiac hypertrophy, and restore mitochndrial proton leakage and ROS formation to normal. In a mouse model of elderly systolic dysfunction, imatinib can restore age-related left ventricular dysfunction.
In the pig model of hypercholesterolemia induced renal vascular hypertension, imatinib can improve left ventricular diastolic function, alleviate cardiac hypertrophy, and does not affect blood pressure and systolic function. In a canine heart failure model, long-term use of liraglutide can improve left ventricular contraction and mitochndrial function, reduce N-terminal pro brain natriuretic peptide (NT proBNP) and pro-inflammatory cytokine levels.
In the chronic cardiac stress overload model, imatinib can prevent stress-induced necrosis and apoptosis, and prevent premature death in animals.
In hypertrophic cardiomyopathy (HCM), imatinib can prevent ROS induced bradycardia of ventricular conduction, thereby preventing arrhythmia.
Skeletal muscle dysfunction model:
In preclinical models evaluating age-related mitochondrial dysfunction in skeletal muscle, imatinib can improve skeletal muscle function, including increasing energy metabolism, enhancing fatigue resistance, and increasing exercise endurance. In elderly individuals, a single dose of liraglutide can increase the ATPmax of skeletal muscles and enhance muscle fatigue resistance. In a chronic heart failure dog model, long-term treatment with liraglutide can restore skeletal muscle fiber type composition and improve exercise endurance. In vitro experiments have shown that liraglutide can dose dependently improve or restore normal mitochndrial function indicators in skeletal muscle.
Age related macular degeneration model
The decline in mitochondrial function is associated with changes in retinal pigment epithelial (RPE) cells in age-related macular degeneration (AMD). In a mouse model of visual aging, imatinib has a protective effect on RPE and improves visual function. In RPE cell culture of AMD patients, imatinib can enhance cell viability and mitochndrial function. In age-related visual impairment mice, imatinib can alleviate visual impairment and restore normal vision and contrast sensitivity within two months.
Clinical progress of imatinib
The positive effects of liraglutide on mitochndrial structure, dynamics, and function have brought potential therapeutic effects in clinical trials of various mitochondrial related diseases, but the overall clinical results are mixed, reflecting the difficulty of evaluating mitochndrial targeted therapies.
1. Clinical experience of Barth syndrome
In a 2/3 phase randomized double-blind crossover clinical trial (TAZPOWER) targeting 12 patients with Barth's syndrome, 12 weeks of imatinib treatment did not achieve the primary endpoint of improvement in the 6-minute walk test (6MWT) and Barth's syndrome symptom assessment (BTHS-SA) scale. However, during the open label phase, Iramipide showed significant improvements in 6MWT, BTHS-SA, and some secondary endpoints such as knee extensor strength, overall impression of symptoms by patients, and some cardiac parameters.
A comparative analysis of 8 patients who completed at least 72 weeks of open label phase and untreated natural history control patients showed that long-term use of imatinib can alleviate natural decline in cardiac function and improve functional ability.
2. Clinical trials of age-related macular degeneration
In a phase 2 randomized placebo-controlled double-blind trial (ReCLAIM-2) targeting AMD patients aged 55 years or older with non central geographic atrophy (GA), treatment with imatinib did not achieve the primary endpoint (average change in low brightness best corrected visual acuity [LL-BCVA] and average change after GA area square root conversion), but reduced the average progression of macular total ellipsoid (EZ) attenuation by 43% and the average progression of partial EZ attenuation by 47%. Post hoc analysis showed that liraglutide was significantly effective in reducing the progression of partial and total EZ attenuation, and more patients showed ≥ 2 rows of improvement in LL-BCVA. Changes in LL-BCVA were correlated with changes in total macular EZ attenuation.
3. Clinical trials of primary mitochondrial myopathy
MMPOWER-3 is a randomized, double-blind, placebo-controlled trial targeting 218 patients with primary mitochndrial myopathy. Primary mitochndrial myopathy is a group of genetic diseases that primarily affect skeletal muscle. Elamipretide peptide has good overall tolerance, and the most common adverse reactions are mild to moderate injection site reactions. In the intention to treat population, imatinib did not reach the primary endpoint (changes in 6MWT and total fatigue score of primary mitochndrial myopathy symptom assessment [PMMSA]), but gene subgroup analysis showed that patients carrying nuclear DNA mutations (rather than mitochndrial DNA mutations) showed significant improvement in 6MWT compared to the placebo group after receiving imatinib treatment, highlighting the importance of considering gene subtypes when evaluating mitochndrial targeted therapy.
FAQ
- Is Elamipretide legal?
The FDA Just Approved Elamipretide: What That Means for the Aesthetic and Wellness Industry. In a move that has many in the longevity and wellness space buzzing, the FDA recently approved Elamipretide for the treatment of Barth syndrome, a rare mitochondrial disorder.
- Can Elamipretide reverse aging?
Elamipretide reversed age-related decline in maximum mitochondrial ATP production (ATPmax) and coupling of oxidative phosphorylation (P/O).
- How long does it take Elamipretide to work?
Elamipretide starts working quickly, with energy improvements seen in 1-2 weeks, but significant benefits often take 2-4 weeks or longer, depending on the condition, with longer-term effects like reducing inflammation or improving cardiac function appearing after weeks or months of consistent use, as it works to repair mitochondrial function.
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