SS-31 50mg

SS-31, also known as elamipretide, is a synthetic peptide designed to enhance mitochondrial function and overall cellular energy production. It achieves this by stabilizing cardiolipin, a crucial component of the inner mitochondrial membrane, thereby improving ATP synthesis and reducing oxidative stress.

Chemical Structure

• Sequence: D-Arg-Tyr(2,6-diMe)-Lys-Phe
• Molecular Formula: C₃₂H₄₉N₉O₅
• Molecular Weight: 639.8 g/mol
• CAS Number: 736992-21-5
• Synonyms: Elamipretide, MTP-131, Bendavia

SS-31 Research

Mitochondria Improvement

Primary mitochondrial diseases (PMDs) are among the most common inherited disorders worldwide. These conditions result from dysfunction in the mitochondria, the cell’s energy-producing organelles. Symptoms vary widely depending on the disease form, but organ systems with high energy demands—such as the nervous system, heart, and kidneys—are typically the most affected. Muscle involvement and exercise intolerance are nearly universal among those with mitochondrial disorders. Common symptoms include fatigue, difficulty exercising, and seizures.

PMDs, and mitochondrial diseases in general, primarily involve impaired ATP production. ATP serves as the cell’s energy currency and is essential for nearly all cellular functions. Stabilizing ATP production in mitochondrial diseases has long been a clinical objective. The development of the peptide SS-31 offers promising progress toward achieving this goal.

Initial evidence for SS-31’s ability to restore energy production in PMDs came from animal studies. In one study, rats with kidney ischemia-reperfusion injury—a non-genetic form of mitochondrial damage—were treated with SS-31. The peptide preserved kidney structure, accelerated ATP recovery, and reduced cell death and tissue necrosis. Subsequent mouse studies showed that SS-31 binds to cardiolipin in the inner mitochondrial membrane and can alleviate symptoms of mitochondrial dysfunction regardless of the underlying cause. Additionally, SS-31 has demonstrated potential to improve age-related mitochondrial decline. These findings helped secure orphan drug status from the FDA for SS-31 and facilitated the start of clinical trials.

In phase II human trials, SS-31 improved exercise performance after only five days of treatment and showed no major safety concerns. However, these trials did not conclusively demonstrate clinical benefit. It is believed that this outcome was due to the selection of trial endpoints rather than a true lack of efficacy. Experts, including Dr. Bruce Cohen, director of the Neurodevelopment Science Center at Akron Children’s Hospital, remain optimistic and advocate for further research. Ongoing and planned trials are exploring alternative endpoints and derivatives of SS-31, signaling sustained interest in its therapeutic potential.

Currently, SS-31 is being investigated in various human diseases through multiple trial designs. It is considered safe for use in humans and may be prescribed under compassionate use exceptions for patients lacking other treatment options. While further clinical validation is pending, SS-31 is expected to become part of standard care for several conditions in the near future.

Ischemia and Heart Failure

One of the most promising secondary uses of SS-31 is in treating heart failure. Mitochondrial dysfunction is a known contributor to worsening heart failure in a self-perpetuating cycle. Research on human heart tissue treated with SS-31 has shown significant improvements in mitochondrial oxygen utilization and ATP production components. Interestingly, some studies suggest SS-31 may act through mechanisms beyond cardiolipin interaction, warranting further investigation.

Animal studies demonstrate that chronic SS-31 treatment can improve left ventricular function in advanced heart failure. Improvements in mitochondrial respiration and ATP synthesis closely correlated with enhanced cardiac performance, suggesting SS-31 may offer long-term benefits by improving energy dynamics and reducing harmful cardiac remodeling.

Clinical trials examining SS-31 use in acute heart attacks (ST-segment elevation myocardial infarction) found that the peptide significantly lowered levels of HirA2, a marker of heart muscle cell apoptosis. These results indicate that SS-31 could reduce injury extent and preserve cardiac tissue during acute events.

Diabetes and Mitochondrial Dysfunction

Diabetes, especially type 2, is increasingly recognized as a complex condition involving mitochondrial impairment. Addressing mitochondrial dysfunction may help mitigate long-term complications like oxidative damage to small blood vessels. Human studies show SS-31 markedly reduces reactive oxygen species production, suggesting it can decrease oxidative damage associated with mitochondrial dysfunction and potentially slow microvascular disease progression in diabetes.

Additionally, SS-31 was found to increase SIRT1 levels, a protein linked to improved insulin sensitivity and reduced inflammation in type 2 diabetes, supporting its potential therapeutic role.

Anti-Inflammatory Effects

A common theme across SS-31 research is its ability to reduce inflammation by regulating reactive oxygen species (free radicals), which contribute to oxidative stress in chronic diseases such as diabetes and heart disease. Cell culture studies reveal that SS-31 lowers expression of FIS1, a mitochondrial protein involved in mitochondrial division. Elevated FIS1 is associated with neurodegenerative diseases and certain cancers, indicating dysfunctional mitochondrial division and inflammation.

Animal models provide additional evidence that SS-31 reduces inflammatory markers including CD-36, activated MnSOD, NADPH oxidase activity, and NF-kappaB p65—a key regulator of cellular inflammation implicated in diseases like rheumatoid arthritis and inflammatory bowel disease. By preventing inflammasome activation in mitochondria, SS-31 helps maintain normal ATP production and prevents excessive reactive oxygen species generation.

Summary

Originally developed to address mitochondrial dysfunction in inherited mitochondrial diseases, SS-31 also shows promise in regulating mitochondria-driven inflammation. Despite initial phase II trial setbacks, ongoing research is focused on testing the peptide in a variety of conditions with more appropriate outcome measures. SS-31 may hold the key to treating mitochondrial dysfunction across diseases such as Alzheimer’s, Parkinson’s, heart disease, diabetes, and kidney disease.

Dr. Bruce H. Cohen, a leading expert in mitochondrial disease research and clinical trials, has contributed significantly to SS-31 studies. While he does not endorse or promote the product commercially, his work helps advance understanding of mitochondrial therapeutics. Akron Children’s Hospital, where Dr. Cohen leads research efforts, is among the top institutions conducting mitochondrial clinical trials.

Research Applications

SS-31 has been studied for its potential therapeutic effects in various conditions associated with mitochondrial dysfunction, including:

• Neurological Disorders: Alzheimer’s disease, Parkinson’s disease
• Metabolic Diseases: Diabetes, nonalcoholic fatty liver disease
• Cardiovascular Conditions: Heart failure
• Kidney Disease: Chronic kidney disease
• Muscle Disorders: Mitochondrial myopathies

Clinical trials have shown that SS-31 can improve mitochondrial function and reduce oxidative stress in these conditions.

Safety and Usage

SS-31 is currently available for research purposes only and is not approved for human consumption. It is typically provided in a lyophilized (powder) form to ensure maximum stability. Researchers interested in studying SS-31 should adhere to appropriate safety protocols and ethical guidelines.

References

• Szeto HH, et al. Mitochondria-targeted peptide accelerates ATP recovery and reduces ischemic kidney injury. J Am Soc Nephrol. 2011;22(6):1041-1052. doi:10.1681/ASN.2010080808.  
• Siegel MP, et al. Mitochondrial targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice. Aging Cell. 2013;12(5):763-771. doi:10.1111/acel.12102.  
• 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. doi:10.1681/ASN.2012121216.  
• Chatfield KC, et al. Elamipretide improves mitochondrial function in the failing human heart. JACC Basic Transl Sci. 2019;4(2):147-157. doi:10.1016/j.jacbts.2018.12.005.  
• Karaa A, Haas R, Goldstein A, Vockley J, Weaver WD, Cohen BH. Randomized dose-escalation trial of elamipretide in adults with primary mitochondrial myopathy. Neurology. 2018;90(14):1212-1221. doi:10.1212/WNL.0000000000005255.  
• PhD AM. Elamipretide failed to meet promise of earlier trial results for primary mitochondrial myopathy. Mitochondrial Disease News. January 10, 2020. https://mitochondrialdiseasenews.com/2020/01/10/elamipretide-failed-to-meet-promise-of-earlier-trial-results-for-primary-mitochondrial-myopathy-data-show/ (accessed April 6, 2020). 
• Could elamipretide become the first treatment option for primary mitochondrial myopathy? Neurology Live. https://www.neurologylive.com/clinical-focus/could-elamipretide-treatment-option-primary-mitochondrial-myopathy (accessed April 6, 2020).  
• Sabbah HN, Gupta RC, Kohli S, Wang M, Hachem S, Zhang K. Chronic therapy with elamipretide (MTP-131), a novel mitochondria-targeting peptide, improves left ventricular and mitochondrial function in dogs with advanced heart failure. Circ Heart Fail. 2016;9(2):e002206. doi:10.1161/CIRCHEARTFAILURE.115.002206.  
• Hortmann M, et al. The mitochondria-targeting peptide elamipretide diminishes circulating HtrA2 in ST-segment elevation myocardial infarction. Eur Heart J Acute Cardiovasc Care. 2019;8(8):695-702. doi:10.1177/2048872617710789.  
• Escribano-Lopez I, et al. The mitochondrial antioxidant SS-31 increases SIRT1 levels and ameliorates inflammation, oxidative stress and leukocyte-endothelium interactions in type 2 diabetes. Sci Rep. 2018;8(1):1-10. doi:10.1038/s41598-018-34251-8.  
• Mo Y, et al. SS-31 reduces inflammation and oxidative stress through the inhibition of Fis1 expression in lipopolysaccharide-stimulated microglia. Biochem Biophys Res Commun. 2019;520(1):171-178. doi:10.1016/j.bbrc.2019.09.077.  
• Hou Y, et al. The antioxidant peptide SS31 prevents oxidative stress, downregulates CD36 and improves renal function in diabetic nephropathy. Nephrol Dial Transplant. 2018;33(11):1908-1918. doi:10.1093/ndt/gfy021.  
• Hou Y, et al. Mitochondria-targeted peptide SS-31 attenuates renal injury via an antioxidant effect in diabetic nephropathy. Am J Physiol Renal Physiol. 2015;310(6):F547-F559. doi:10.1152/ajprenal.00574.2014.