Description

SS-31

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Peptide Partners Manufacturer Id: WF03

Batch Id:  SY20250806

 

Overview

(For educational purposes only)

SS-31, also known as elamipretide (formerly Bendavia® or MTP-131), is a synthetic, mitochondria-targeted tetrapeptide designed for selective binding to cardiolipin on the inner mitochondrial membrane. Initially developed to protect and restore mitochondrial structure and function, SS-31 has demonstrated potent antioxidant, cytoprotective, and bioenergetic effects across multiple organ systems, particularly in tissues subject to energetic or oxidative stress.[1][2][3]

Molecular Properties and Structure

• Amino Acid Sequence: D-Arg-2′,6′-dimethylTyr-Lys-Phe-NH2 (H-D-Arg-Dmt-Lys-Phe-NH2)[3][1]

• Molecular Formula: C32H49N9O5[2][3]

• Molecular Weight: 639.8 g/mol[2][3]

• CAS Number: 827026-02-2[3]

• PubChem CID: 53392797[4]

• Discovery Year: ~2004-2005 (preclinically described; clinical development ongoing)[5][1]

Mechanism of Action

SS-31 is distinguished by its highly polar peptide backbone and net positive charge, arising from its N-terminal D-arginine and lysine residues, which facilitate selective localization to and binding of cardiolipin—a phospholipid unique to the mitochondrial inner membrane. The peptide demonstrates affinity driven by both electrostatic and hydrophobic interactions, concentrating SS-31 at the mitochondrial membrane in a membrane potential-independent manner.[6][7][8][1]

Upon binding cardiolipin, SS-31:

• Inhibits oxidative damage to cardiolipin, thereby preserving the optimum structure of mitochondrial cristae and promoting efficient electron transport chain function.[8][3]

• Scavenges mitochondrial reactive oxygen species (ROS), protecting against hydrogen peroxide, hydroxyl radical, and peroxynitrite-mediated damage, largely due to its dimethyltyrosine residue.[7][1][2]

• Reduces mitochondrial proton leak and improves ATP synthesis efficiency in aged or stressed tissues.[9]

• Modulates mitochondrial membrane biophysical and electrostatic properties, protecting against disturbances during ischemia, calcium overload, or metabolic stress without destabilizing the mitochondrial bilayer.[10][6]

• Reduces apoptotic cell death by supporting mitochondrial integrity.

Biological Effects and Clinical Applications

SS-31 has shown promising protective results in numerous preclinical models:

• Cardiac protection: Reduces infarct size and improves post-ischemic cardiac function.

• Renal protection: Ameliorates kidney injury by preserving mitochondrial function and structure.[8]

• Skeletal muscle, retina, and neuroprotection: Enhances bioenergetics and reduces oxidative stress in diverse tissues subject to age- or disease-related decline.[3]

• Potential in mitochondrial myopathies, neurodegenerative diseases (including Alzheimer’s), heart failure, renal disease, and acute organ injuries.

• Clinical translation: SS-31/elamipretide has advanced to clinical trials, especially for mitochondrial myopathy (primary mitochondrial disease), heart failure, and age-related macular degeneration, among other uses.

• Pharmacokinetics: SS-31 has a plasma half-life of 4 hours in dogs, is water-soluble, cell-permeable, and rapidly accumulates in mitochondria after systemic administration.[2]

Key Advantages

• Selective delivery and concentration in mitochondria via cardiolipin binding.

• Does not disrupt, but rather preserves, mitochondrial membrane structure and biophysical properties at pharmacological concentrations.[6]

• Mechanistically distinct from traditional antioxidants; acts at the site of maximal ROS generation and electron transport.[7]

Safety and Limitations

SS-31 has appeared safe in animal and early human studies; however, as of 2025, large-scale clinical data to support routine therapeutic use is still evolving. Oral and parenteral formulations (including subcutaneous and intravenous) are under investigation.[2][3]

Conclusion

SS-31 (elamipretide) represents a rationally designed, mitochondria-targeted antioxidant peptide that is highly selective for cardiolipin, promoting mitochondrial integrity, energy production, and cell survival in response to stress. Its track record in preclinical models and early clinical trials highlights its promise for treating diseases rooted in mitochondrial dysfunction and oxidative stress.SS-31, also known as elamipretide, is a synthetic tetrapeptide engineered to target mitochondria and protect them from oxidative and structural damage. Its amino acid sequence is D-Arg-dimethylTyr-Lys-Phe-NH2, and it has a molecular formula of C32H49N9O5 with a molecular weight of about 639.8 g/mol. The peptide selectively binds to cardiolipin within the inner mitochondrial membrane, stabilizing mitochondrial cristae structure and mitigating the formation of reactive oxygen species. SS-31’s mechanism involves both antioxidant activity (largely from its dimethyltyrosine residue) and direct preservation of bioenergetics, making it distinct from standard antioxidants that lack mitochondrial specificity.[1][7][8][3][2]

Preclinical and early clinical studies demonstrate that SS-31 improves mitochondrial bioenergetics, lowers cell death, and is protective in models of heart, kidney, muscle, and neurodegenerative diseases. Its pharmacokinetic profile supports potential use in both acute and chronic settings, as SS-31 is water-soluble, cell-permeable, and concentrates at the mitochondrial site after administration. With a discovery history dating to about 2004, SS-31 remains in active clinical development for conditions such as mitochondrial diseases, heart failure, and age-related disorders, though large-scale clinical evidence is still emerging. Its design and function exemplify targeted peptide strategies for addressing mitochondrial dysfunction and oxidative stress at the source.[1][7][8][3][2]

 

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1. https://pmc.ncbi.nlm.nih.gov/articles/PMC11409442/        

2. https://www.alzdiscovery.org/uploads/cognitive_vitality_media/SS-31-Cognitive-Vitality-For-Researchers.pdf         

3. https://peptidesociety.org/_template-monographs-8/           

4. https://pubchem.ncbi.nlm.nih.gov/compound/dsip 

5. https://pmc.ncbi.nlm.nih.gov/articles/PMC7334473/ 

6. https://www.biorxiv.org/content/10.1101/735001v1.full.pdf   

7. https://www.nature.com/articles/s41598-018-34251-8      

8. https://onlinelibrary.wiley.com/doi/10.1155/2022/1295509      

9. https://elifesciences.org/articles/75531 

10. https://www.sciencedirect.com/science/article/pii/S0021925817502768 

11. https://www.sciencedirect.com/science/article/pii/S2214031X25000592