SS-31

SS-31 Peptide - 10mg

SS-31 (Elamipretide) is a small, synthetic tetrapeptide with the formula D-Arg-Dmt-Lys-Phe-NH2. Its unique structure allows it to easily penetrate cellular membranes, targeting and accumulating within the inner mitochondrial membrane. It is primarily recognized for its ability to stabilize cardiolipin, an essential phospholipid critical for the integrity and function of the electron transport chain (ETC), the system responsible for cellular energy (ATP) production.

The peptide's mechanism of action is believed to reduce the formation of reactive oxygen species (ROS)—or free radicals—by enhancing the efficiency of the ETC. Disruption of cardiolipin structure and function is implicated in various conditions, including neurodegenerative disorders (Alzheimer's, Parkinson's), metabolic diseases (diabetes, nonalcoholic fatty liver disease), and cardiovascular issues (heart failure). SS-31 is a noteworthy compound in research, being one of the first peptides to enter clinical trials for primary mitochondrial myopathy, a group of neuromuscular disorders resulting from mitochondrial damage.

SS-31 Peptide - 10mg Overview

SS-31 (Elamipretide) is a synthetic tetrapeptide (D-Arg-Dmt-Lys-Phe-NH2) developed specifically for its high-affinity binding to cardiolipin on the inner mitochondrial membrane. This compound has been extensively investigated for its potential to mitigate oxidative stress, mitochondrial dysfunction, and age-related cellular decline.

The peptide's design enables it to rapidly permeate mitochondrial membranes. Once bound to cardiolipin, it helps stabilize mitochondrial cristae, leading to a reduction in reactive oxygen species (ROS) formation and an enhancement of ATP synthesis. Unlike traditional antioxidants that scavenge free radicals, SS-31 operates by improving the overall efficiency of the electron transport chain and preserving critical mitochondrial structure and function. Its small size, cationic charge, and aromatic-rich residues facilitate its rapid and selective accumulation within mitochondria across various cell types, establishing it as a valuable tool for research into mitochondrial health and aging.

SS-31 Peptide Structure

The chemical structure of SS-31 is a synthetic tetrapeptide composed of four amino acids: D-Arginine, Dimethyltyrosine (Dmt), Lysine, and Phenylalanine-Amide.

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

The presence of the non-standard amino acid, Dimethyltyrosine (Dmt), and the D-amino acid configuration, is critical to the peptide's ability to selectively target and interact with the anionic cardiolipin phospholipid unique to the inner mitochondrial membrane. This targeted action is the basis for its mitochondrial-stabilizing and bioenergetic-enhancing effects observed in research.

SS-31 Peptide Research

Mitochondria Improvement

Primary Mitochondrial Diseases (PMDs) represent a significant group of inherited metabolic disorders characterized by defects in the mitochondria's energy-producing machinery. Since organs with high metabolic demands—such as the brain, heart, and skeletal muscles—are most vulnerable, common clinical manifestations include muscle weakness, fatigue, exercise intolerance, and seizures.

A defining feature of PMDs and other mitochondrial disorders is deficient ATP production, which critically impairs nearly all biological functions. Stabilizing and restoring ATP synthesis has been a major focus in mitochondrial research. Early animal studies provided compelling evidence that SS-31 could restore energy production. For instance, in rats subjected to ischemia-reperfusion injury (a model of non-genetic mitochondrial dysfunction in the kidneys), SS-31 treatment was shown to accelerate ATP recovery, preserve kidney tissue structure, and reduce cell necrosis. Further studies confirmed that SS-31's binding to cardiolipin in the inner mitochondrial membrane can mitigate mitochondrial disease symptoms across various underlying causes, with additional data suggesting a counteractive effect against age-related mitochondrial dysfunction.

These highly promising preclinical results led to SS-31 being granted Orphan Drug Status by the FDA, paving the way for human clinical evaluation. While Phase II human trials showed that SS-31 could enhance exercise performance within five days with an excellent safety profile, subsequent Phase III trials did not meet their primary endpoints. However, many experts suggest that the trial design, particularly the selected endpoints, may not have been optimal. Ongoing research continues to explore its therapeutic potential, and SS-31's strong safety profile has allowed it to be utilized in compassionate use programs for patients with limited treatment alternatives.

Research Area

Observed Benefit in Experimental Models

Proposed Mechanism of Action

Mitochondrial Health

Accelerated ATP recovery, preserved tissue structure, improved exercise tolerance

Stabilizes cardiolipin, enhances electron transport chain efficiency

Ischemia/Heart Failure

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

Supports mitochondrial respiration, prevents cardiolipin restructuring, limits cardiac tissue damage

Diabetes

Reduced reactive oxygen species (ROS) production, elevated SIRT1 levels

Lessens oxidative stress, improves insulin sensitivity, reduces inflammation

Anti-Inflammation

Downregulation of FIS1, reduced inflammatory cytokine CD-36, inhibited NF-kappaB p65 signaling

Modulates ROS, decreases chronic inflammatory signaling, improves cellular redox balance

Ischemia

SS-31 shows significant promise in the treatment of conditions involving ischemia-reperfusion injury, such as heart failure. Cardiac performance decline is strongly linked to mitochondrial dysfunction, creating a negative feedback loop. Research on human heart tissue has demonstrated that SS-31 significantly enhances mitochondrial oxygen flux and the activity of ATP-producing enzymes. Interestingly, some findings suggest that SS-31 has additional mechanisms of action beyond cardiolipin stabilization, as the effect was observed even when cardiolipin restructuring was chemically prevented.

In canine models of advanced heart failure, chronic SS-31 treatment resulted in improved left ventricular function. These functional improvements were directly correlated with enhanced mitochondrial respiration and maximal ATP synthesis, suggesting that SS-31 holds potential as a long-term therapeutic agent for optimizing cellular energy metabolism and reducing cardiac remodeling in severe heart disease. Furthermore, clinical trials in patients with ST-segment elevation myocardial infarction (STEMI) indicated that SS-31 can significantly reduce levels of HtrA2, a key biomarker for cardiomyocyte apoptosis, suggesting a role in limiting cardiac tissue damage and preserving heart function following acute heart injury.

Diabetes

While historically viewed through the lens of insulin deficiency, Type 2 diabetes is a complex disorder where mitochondrial dysfunction plays a critical role, particularly in the development of long-term complications like oxidative damage to microvessels.

A human study demonstrated that SS-31 treatment resulted in a notable reduction in reactive oxygen species (ROS) production, suggesting a mechanism to lessen the oxidative stress associated with mitochondrial impairment in diabetes. This effect may help slow or prevent the progression of microvascular complications. The same study also observed that SS-31 elevated levels of SIRT1, a protein linked to enhanced insulin sensitivity and reduced inflammation in Type 2 diabetes models.

Reduces Inflammation

A consistent finding across SS-31 research is its profound anti-inflammatory potential, largely mediated through its ability to modulate reactive oxygen species (ROS) and reduce the oxidative stress underlying chronic diseases. In vitro studies show that SS-31 helps lower inflammation by downregulating FIS1 expression, a mitochondrial protein whose elevated levels are associated with impaired mitochondrial division, neurodegeneration, and various cancers.

Further in vivo evidence in mouse models indicates that SS-31 reduces inflammatory biomarkers such as the cytokine CD-36, suppresses the expression of activated MnSOD, inhibits NADPH oxidase activity, and dampens NF-kappaB p65 signaling. The inhibition of NF-kappaB, a central mediator of persistent cellular inflammation, is particularly significant, underscoring SS-31’s value as a powerful mitochondrial-targeted anti-inflammatory research agent.

SS-31 Summary

SS-31 initially gained prominence for its role in regulating mitochondrial function in primary mitochondrial diseases. However, compelling evidence now highlights its broad potential to modulate mitochondria-driven inflammation. The peptide continues to be a focal point of research for its capacity to enhance mitochondrial efficiency and boost ATP production, thereby improving overall cellular bioenergetics.

Despite mixed results in initial Phase III clinical trials, many experts believe this was due to limitations in endpoint selection rather than a true lack of efficacy. With ongoing Phase II and planned Phase III trials exploring a wider range of disease models and clinical outcomes, SS-31 remains a critical molecule in mitochondrial research. It is anticipated to significantly advance our understanding of mitochondrial dysfunction and contribute to the development of next-generation therapies for conditions such as heart disease, diabetes, neurodegenerative disorders, and other diseases linked to impaired mitochondrial health.

Article Author

This review was researched, compiled, and formatted by Dr. Bruce H. Cohen, M.D., Ph.D. Dr. Cohen is a highly respected authority in the field of mitochondrial medicine and neurodevelopmental disorders. As the Director of the Neurodevelopmental Science Center at Akron Children’s Hospital, he has made substantial contributions to the clinical study and treatment of mitochondrial dysfunction. His research focuses on translating mitochondrial science into effective therapeutic strategies designed to improve cellular energy metabolism and patient outcomes.

Scientific Journal Author

Dr. Hazel H. Szeto, M.D., Ph.D., is the principal researcher and original developer of the mitochondrial-targeted peptide SS-31 (Elamipretide). Her pioneering work has been instrumental in advancing the foundational understanding of cardiolipin stabilization, oxidative stress reduction, and mitochondrial energy regulation. Through collaborative research with scientists including A.V. Birk, K. Zhao, S. Luo, D.A. Brown, and R.A. Kloner, Dr. Szeto helped establish the core scientific principles behind SS-31 and its potential applications across cardiovascular, neurodegenerative, and metabolic research.

Acknowledgment: This section is intended solely to recognize the academic and scientific work of Dr. Szeto and her collaborators. It should not be considered an endorsement or promotion of this product. Montreal Peptides Canada maintains no affiliation, sponsorship, or professional association with Dr. Szeto or any of the cited researchers.

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 products are prepared via lyophilization (freeze-drying), a process that ensures stability during shipping for approximately 3–4 months. After the peptide is reconstituted with bacteriostatic water, it must be stored in a refrigerator to maintain maximum effectiveness. Once in solution, most peptides remain stable for up to 30 days.

Lyophilization, or cryodesiccation, is a specialized dehydration method where the peptide is frozen, and the water is removed under low pressure. This causes the water to sublimate (transition directly from ice to gas), leaving behind a stable, white crystalline structure known as the lyophilized peptide. This powder can be safely stored at room temperature until it is ready for reconstitution. For extended storage periods lasting several months to years, it is highly recommended to store the lyophilized peptide in a freezer at -80 degrees C (-112 degrees F). Freezing under these conditions helps maintain the peptide’s structural integrity and ensures long-term stability.

Upon receiving the product, it is essential to keep the peptide cool and protected from light. For short-term use (a few days to a few months), refrigeration below 4 degrees C (39 degrees F) is adequate. Lyophilized peptides typically remain stable at room temperature for several weeks, which is acceptable for shorter storage durations before use.

Best Practices For Storing Peptides

Proper storage is crucial for maintaining the accuracy and reliability of results in laboratory research. Following correct procedures prevents contamination, oxidation, and degradation, thereby ensuring the peptide remains stable and effective over time.

• Upon Receipt: Store lyophilized peptides cool and shielded 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 stability.
• Avoid Freeze-Thaw Cycles: Repeated temperature fluctuations accelerate degradation. Do not use frost-free freezers as they undergo temperature variations during defrosting.

Preventing Oxidation and Moisture Contamination

Protecting peptides from air and moisture exposure is vital to maintaining stability. Moisture contamination is a key concern, especially when removing a cold vial from the freezer. Always allow the vial to reach room temperature before opening it to prevent condensation from forming on the peptide powder or inside the container.

Minimizing air exposure is equally important. The container should be kept closed as much as possible, and after removing the required amount, it should be promptly resealed. For sensitive peptides, storing the remainder under a dry, inert gas atmosphere (such as nitrogen or argon) can further prevent oxidation. Peptides containing cysteine (C), methionine (M), or tryptophan (W) residues are particularly susceptible to air oxidation and require extra care. To preserve long-term stability, it is best practice to aliquot the total peptide quantity into smaller, single-use portions. This minimizes repeated exposure to air and temperature changes, significantly prolonging the peptide's integrity.

Storing Peptides In Solution

Peptide solutions have a substantially shorter shelf life and are more vulnerable to bacterial degradation than their lyophilized form. Peptides containing cysteine (Cys), methionine (Met), tryptophan (Trp), aspartic acid (Asp), glutamine (Gln), or N-terminal glutamic acid (Glu) residues degrade more rapidly in solution.

If storage in solution is necessary, use sterile buffers with a pH between 5 and 6. The solution should be aliquoted to minimize freeze-thaw cycles. Under refrigerated conditions at 4 degrees C (39 degrees F), most peptide solutions are stable for up to 30 days. Less stable peptides should be kept frozen until immediate use is required.

Peptide Storage Containers

Storage containers must be clean, durable, and chemically resistant, with appropriate sizing to minimize excess air space. High-quality glass vials offer the best overall combination of clarity, stability, and chemical inertness for long-term peptide storage. While glass is preferred, peptides are often shipped in plastic vials to reduce breakage risk. Safe transfer between plastic and glass vials is acceptable to meet specific storage or handling needs.

Peptide Storage Guidelines: General Tips

Adhering to these best practices will help maintain peptide stability and prevent degradation:

• Store peptides in a cold, dry, and dark environment.
• Avoid repeated freeze-thaw cycles to protect structural integrity.
• Minimize exposure to air to reduce oxidation risk.
• Protect from light to prevent structural changes.
• Do not store peptides in solution long term; keep them lyophilized whenever possible.
• Aliquot peptides based on experimental needs to prevent unnecessary handling and exposure.