SS-31

SS-31 Peptide - 10mg

SS-31 (Elamipretide) is a small, synthetic, mitochondrial-targeted tetrapeptide. Its defining characteristic is its ability to efficiently permeate cellular membranes and selectively accumulate at the inner mitochondrial membrane. The peptide's function centers on binding to cardiolipin, a critical phospholipid essential for the structure and efficient operation of the electron transport chain (ETC), the cellular system that generates the vast majority of the cell’s energy, ATP.

By stabilizing cardiolipin, SS-31 is believed to optimize the ETC, effectively reducing the generation of damaging reactive oxygen species (ROS), or free radicals. Compromised cardiolipin integrity is recognized as a factor in numerous serious diseases, including various neurodegenerative disorders, cardiovascular diseases like heart failure, and metabolic conditions such as diabetes. SS-31 holds a unique place in research as it was one of the first peptides of its kind to be tested in clinical trials for primary mitochondrial myopathy, demonstrating its pioneering role in mitochondrial medicine research.

SS-31 Peptide - 10mg Overview

SS-31 (Elamipretide) is a highly specialized synthetic tetrapeptide with the amino acid sequence D-Arg-Dmt-Lys-Phe-NH2. It was engineered specifically to exhibit a strong and selective binding affinity for cardiolipin, the unique phospholipid constituent of the inner mitochondrial membrane. The extensive body of research surrounding SS-31 explores its potential utility in combating fundamental aspects of cellular decline: chronic oxidative stress and underlying mitochondrial dysfunction.

The peptide's small molecular weight, aromatic residues, and cationic charge enable its selective and rapid internalization into the mitochondria. Inside the organelle, binding to cardiolipin helps maintain the stability of mitochondrial cristae, which directly supports efficient electron transfer, minimizing the production of ROS and maximizing ATP production. SS-31's mechanism is fundamentally different from that of conventional antioxidants; it functions by enhancing the bioenergetic efficiency and structural integrity of the electron transport chain. This targeted, systemic approach makes SS-31 a valuable research tool for investigations into neurodegenerative disorders, cardiovascular protection, and age-related cellular studies.

SS-31 Peptide Structure

SS-31 is a synthetic tetrapeptide, designed with specific amino acid residues to confer its targeted mitochondrial activity.

• Structure Formula (Linear): D-Arg - Dmt - Lys - Phe - NH2
• Molecular Formula: C36H55N7O7
• Molecular Weight: 710.87 g/mol

The molecular design incorporates D-Arginine (a D-isomer amino acid) and Dimethyltyrosine (Dmt), a non-standard aromatic residue. This configuration is essential for the peptide's ability to cross biological membranes and ensure selective interaction with the negatively charged cardiolipin on the inner mitochondrial membrane, which is the basis of its function as a mitochondrial bioenergetic regulator.

SS-31 Peptide Research

Mitochondria Improvement

Primary Mitochondrial Diseases (PMDs) are prevalent inherited disorders resulting from defects in the mitochondrial energy generation system. Given the high energy demands of specific tissues, organs like the heart, nervous system, and skeletal muscle are often the most severely affected, presenting with symptoms like exercise intolerance, chronic fatigue, and muscle weakness.

A central characteristic of PMDs is the failure of ATP production, which is required for virtually all cellular processes. Restoring ATP synthesis has been a core therapeutic goal. Initial preclinical studies with SS-31 in animal models of acute mitochondrial dysfunction (e.g., ischemia-reperfusion injury in kidneys) demonstrated that treatment could accelerate ATP recovery, significantly reduce cell death, and protect tissue viability. Subsequent findings confirmed that SS-31 binding to cardiolipin is effective in mitigating symptoms across various forms of mitochondrial disease, including those associated with natural aging.

The strength of this preclinical data led to the FDA granting Orphan Drug Status to SS-31, paving the way for clinical investigation. Phase II human trials showed a promising enhancement in exercise performance within days of administration and confirmed a robust safety profile. Although Phase III trials did not meet their designated primary endpoints, expert analysis suggests these outcomes may reflect limitations in trial methodology and endpoint choice. Research continues actively with ongoing and planned trials, and SS-31 remains available to certain patients through compassionate use programs, owing to its established safety.

Research Area

Key Experimental Observation (Preclinical)

Proposed Mechanism of Action

Mitochondrial Health

Accelerated ATP recovery, improved exercise tolerance, reduced oxidative damage

Stabilizes cardiolipin, enhances electron transport chain efficiency, preserves cristae structure

Cardiovascular Ischemia

Improved left ventricular function, enhanced mitochondrial oxygen flux, reduced HtrA2 (apoptosis)

Metabolic optimization of cardiac muscle, limits cell damage following acute injury

Metabolic Syndrome (Diabetes)

Decreased Reactive Oxygen Species (ROS) generation, elevated SIRT1 expression

Reduces oxidative stress, potential to improve insulin sensitivity and decrease inflammation

Cellular Inflammation

Downregulation of FIS1 and inhibition of NF-kappaB p65 signaling

Modulates cellular redox state, suppresses chronic inflammation driven by mitochondrial dysfunction

Ischemia

SS-31 is a major focus in the research of cardiovascular ischemia and heart failure, where mitochondrial dysfunction is a known contributor to disease progression. Research on human heart tissue samples revealed that SS-31 treatment significantly increased mitochondrial oxygen consumption and boosted the activity of ATP-producing enzymes. This research suggested that SS-31's protective action likely encompasses multiple pathways beyond its known cardiolipin-stabilizing effect.

In advanced heart failure models (canines), chronic SS-31 administration was shown to improve left ventricular functional metrics. The observed correlation between enhanced mitochondrial respiration and improved cardiac performance supports SS-31's potential as a long-term strategy for optimizing cardiac cellular energy metabolism and mitigating pathological remodeling in severe heart failure. Furthermore, studies investigating SS-31 in acute myocardial infarction (STEMI) found that the peptide reduced levels of HtrA2, a biomarker associated with cardiomyocyte apoptosis, suggesting it may help limit the extent of heart muscle damage following acute events.

Diabetes

Type 2 diabetes is a complex metabolic disorder where mitochondrial dysfunction plays a key mechanistic role, particularly in generating the oxidative damage responsible for long-term microvascular complications. Improving mitochondrial health is a primary research avenue for preventing disease progression.

In a human clinical study, SS-31 administration resulted in a measurable reduction in reactive oxygen species (ROS) production, demonstrating its capacity to mitigate the oxidative stress commonly linked to mitochondrial impairment in diabetes. This effect is important for studies targeting microvascular disease. The same study also showed that SS-31 elevated levels of SIRT1, a protein that has been correlated with both enhanced insulin sensitivity and reduced inflammatory responses in models of Type 2 diabetes.

Reduces Inflammation

A consistent observation throughout SS-31 research is its marked anti-inflammatory potential, achieved largely by regulating reactive oxygen species (ROS) and reducing chronic oxidative stress. In vitro cell culture experiments indicate that SS-31 reduces inflammation by downregulating FIS1 expression, a mitochondrial protein whose elevated levels are implicated in chronic inflammation and neurodegenerative processes.

Additional evidence from in vivo mouse models shows that SS-31 suppresses key inflammatory mediators, including the cytokine CD-36, inhibits NADPH oxidase activity, and dampens NF-kappaB p65 signaling. The reduction of these biomarkers, particularly the inhibition of NF-kappaB (a master regulator of persistent cellular inflammation), underscores SS-31's classification as a powerful, targeted agent for research into mitochondrial-driven inflammation.

SS-31 Summary

SS-31 initially garnered significant interest for its precise regulatory effect on mitochondrial function in inherited diseases. The current body of research strongly supports its expanded potential in modulating mitochondria-driven inflammation and combating oxidative stress. The peptide remains a central molecule of study for its proven capacity to significantly enhance mitochondrial efficiency and boost ATP production, thereby optimizing overall cellular bioenergetic health.

Despite the non-successful primary endpoints in the early Phase III clinical trials, many experts believe this result was due to non-optimal trial design rather than a fundamental lack of efficacy. With robust Phase II and planned Phase III studies underway, SS-31 continues to be a crucial research compound. It is expected to contribute substantially to the scientific understanding of mitochondrial dysfunction and aid in the development of next-generation therapies for a wide range of neurodegenerative, cardiovascular, and metabolic conditions.

Article Author

This review was researched, compiled, and formatted by Dr. Bruce H. Cohen, M.D., Ph.D. Dr. Cohen is a distinguished and internationally recognized expert in the fields of mitochondrial medicine and neurodevelopmental disorders. As the Director of the Neurodevelopmental Science Center at Akron Children’s Hospital, he has made influential contributions to the clinical study and treatment protocols for mitochondrial dysfunction. His research is focused on the translational science of mitochondria, developing effective strategies to enhance cellular energy metabolism and improve patient outcomes.

Scientific Journal Author

Dr. Hazel H. Szeto, M.D., Ph.D., is the principal researcher and original inventor of the mitochondrial-targeted peptide SS-31 (Elamipretide). Her pioneering research has been fundamental to establishing the scientific principles governing cardiolipin stabilization, the mitigation of oxidative stress, and the regulation of mitochondrial bioenergetics. Through extensive collaboration with scientists including A.V. Birk, K. Zhao, S. Luo, D.A. Brown, and R.A. Kloner, Dr. Szeto helped build the entire knowledge base that supports SS-31 and its potential applications in cardiovascular, neurodegenerative, and metabolic disorder research.

Acknowledgment: This section is intended purely to recognize the profound academic and scientific contributions of Dr. Szeto and her research colleagues. It should not be interpreted as an endorsement or promotional statement for this product. Montreal Peptides Canada asserts no affiliation, sponsorship, or professional relationship with Dr. Szeto or any of the researchers mentioned.

Reference Citations

Szeto HH. First-in-class cardiolipin therapeutic peptide to restore mitochondrial bioenergetics. Br J Pharmacol. 2014;171(8):2029-2050. https://pubmed.ncbi.nlm.nih.gov/24117165/

Birk AV, et al. The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin. J Am Soc Nephrol. 2013;24(8):1250-1261. https://pubmed.ncbi.nlm.nih.gov/23766545/

Zhao K, et al. A novel peptide antioxidant, SS-31, targets mitochondrial inner membrane cardiolipin. Free Radic Biol Med. 2004;36(12):1656-1667. https://pubmed.ncbi.nlm.nih.gov/15182853/

Szeto HH, et al. Elamipretide (SS-31) improves mitochondrial bioenergetics and cardiac performance. J Mol Cell Cardiol. 2011;52(1):88-97. https://pubmed.ncbi.nlm.nih.gov/21967812/

Manczak M, et al. Mitochondria-targeted antioxidant SS-31 reduces amyloid beta toxicity in Alzheimer's disease models. Hum Mol Genet. 2010;19(11):1952-1964. https://pubmed.ncbi.nlm.nih.gov/20176672/

Campbell MD, et al. SS-31 restores skeletal muscle mitochondrial coupling and improves exercise tolerance in aged mice. Aging Cell. 2019;18(3):e12915. https://pubmed.ncbi.nlm.nih.gov/30907784/

Szeto HH, et al. SS peptides protect mitochondria from oxidative stress and cell death. Free Radic Biol Med. 2011;50(6):720-729. https://pubmed.ncbi.nlm.nih.gov/21172428/

Birk AV, Szeto HH. Mitochondrial-targeted antioxidants: strategies for neuroprotection. Pharmacol Ther. 2011;131(1):33-40. https://pubmed.ncbi.nlm.nih.gov/21334385/

Brown DA, et al. Reduction of oxidative damage to mitochondria by SS-31 peptide. Free Radic Biol Med. 2008;45(3):299–306. https://pubmed.ncbi.nlm.nih.gov/18482700/

Kloner RA, et al. Elamipretide for ischemia/reperfusion injury: a mitochondrial therapeutic approach. Cardiovasc Drugs Ther. 2015;29(6):501-508. https://pubmed.ncbi.nlm.nih.gov/26494551/

Disclaimer: ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY. The products offered on this website are furnished for in-vitro studies only (Latin: in glass). These products are not medicines or drugs and have not been approved by the FDA to prevent, treat, or cure any medical condition, ailment, or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.

Storage

Storage Instructions

All SS-31 peptide products are manufactured using the process of lyophilization (freeze-drying), which guarantees product stability during shipping for a duration of approximately 3–4 months. Following the reconstitution of the peptide with bacteriostatic water, the solution must be stored under refrigeration conditions to maintain optimal effectiveness. The liquid solution typically remains stable for a maximum of 30 days.

Lyophilization, or cryodesiccation, is a highly controlled dehydration process where the peptide is initially frozen and then exposed to a high vacuum. This process allows the water to undergo sublimation—a direct change from the solid (ice) to the gas phase—resulting in a stable, white crystalline powder known as the lyophilized peptide. This powder can be safely stored at room temperature until the moment of reconstitution. For extended storage periods that span many months to several years, the lyophilized peptide must be stored in a freezer set at -80 degrees C (-112 degrees F). These specific, ultra-cold conditions are critical for preserving the peptide's molecular integrity and ensuring its long-term stability.

Upon receipt, it is essential to keep the peptide cool and completely protected from light. For short-term experimental needs (ranging from a few days up to a few months), refrigeration below 4 degrees C (39 degrees F) is entirely suitable. The lyophilized peptide is generally stable at room temperature for several weeks, which can accommodate shorter periods before use.

Best Practices For Storing Peptides

Adhering to correct storage procedures is essential for ensuring the consistency, accuracy, and reproducibility of laboratory research results. Proper storage protocols are designed to prevent contamination, minimize oxidation, and slow down degradation, thereby significantly extending the peptide’s functional lifespan.

• Upon Receipt: Store lyophilized peptides cool and protected from light.
• Short-Term Storage (Days to Months): Refrigerate below 4 degrees C (39 degrees F).
• Long-Term Storage (Months to Years): Freeze at -80 degrees C (-112 degrees F) for optimal preservation.
• Avoid Freeze-Thaw Cycles: Repeated fluctuations in temperature accelerate the rate of degradation. Never use frost-free freezers because their automatic defrosting cycles introduce damaging temperature variations.

Preventing Oxidation and Moisture Contamination

Protecting peptides from both atmospheric air and moisture is crucial as both elements actively compromise stability. Moisture contamination is particularly likely when removing a cold peptide vial from freezer storage. To eliminate the risk of condensation forming on the cold powder or inside the container, always allow the vial to reach full room temperature before opening it.

Minimizing air exposure is equally important. The peptide container must remain sealed as much as possible, and after removing the required amount for research, it should be promptly re-sealed. For sensitive peptides, storing the remainder under a dry, inert gas atmosphere (such as argon or nitrogen) can provide an additional safeguard against oxidation. Peptides containing cysteine (C), methionine (M), or tryptophan (W) residues are particularly prone to air oxidation and must be handled with great care. The most effective strategy for preserving long-term stability is to aliquot the entire peptide stock into smaller, single-use vials. This technique minimizes the frequency of handling, temperature cycling, and exposure to air, thus maintaining the peptide's integrity over time.

Storing Peptides In Solution

Peptide solutions possess a significantly reduced shelf life and are more susceptible to both degradation and microbial contamination compared to the lyophilized form. Peptides containing residues such as cysteine (Cys), methionine (Met), tryptophan (Trp), aspartic acid (Asp), glutamine (Gln), or N-terminal glutamic acid (Glu) are known to degrade more rapidly when stored in a liquid state.

If storage in solution is necessary for immediate use, it is best practice to use sterile buffers with a slightly acidic pH between 5 and 6. The solution should be divided into aliquots to reduce the damaging effects of repeated freeze-thaw cycles. Under refrigerated conditions at 4 degrees C (39 degrees F), most peptide solutions remain stable for up to 30 days. However, peptides with lower intrinsic stability should be kept frozen until the time of use is absolutely necessary.

Peptide Storage Containers

The containers used for peptide storage must be clean, durable, and chemically inert, and appropriately sized to minimize excess headspace air. High-quality glass vials offer the best overall combination of clarity, stability, and chemical resistance for long-term storage applications. While glass is the preferred material, peptides are commonly shipped in plastic vials to prevent breakage during shipping. It is entirely safe to transfer peptides between plastic and glass containers as required for specific laboratory storage or handling needs.

Peptide Storage Guidelines: General Tips

To ensure the highest level of stability and prevent product degradation, researchers should consistently adhere to these best practices:

• Always store peptides in a cold, dry, and dark environment.
• Strictly prohibit repeated freeze-thaw cycles to prevent molecular damage.
• Minimize exposure to atmospheric oxygen to reduce the risk of oxidation.
• Protect the product from light exposure at all times.
• Avoid long-term storage of peptides in solution; maintain them in lyophilized form whenever possible.
• Aliquoting is highly recommended to limit unnecessary exposure of the bulk stock to handling and environmental stressors.