The SS-31 peptide, also known as elamipretide, is a synthetic tetrapeptide that has been studied for its ability to concentrate in the inner mitochondrial membrane. SS 31 belongs to the Szeto-Schiller (SS) family of peptides, named after Hazel Szeto and Peter Schiller, whose work in the early 2000s produced a series of small, cell-permeable aromatic-cationic peptides. This article explains its structure, what has been investigated and how it differs from other compounds in mitochondrial research.
For laboratory research use only. Not for human or veterinary use. See our research use only policy.
At a glance: SS-31 identity
- Name: SS-31
- Synonyms: Elamipretide, MTP-131, Bendavia
- Sequence: D-Arg-Dmt-Lys-Phe-NH2 (Dmt = 2',6'-dimethyltyrosine)
- Molecular formula: C32H49N9O5
- Molecular weight: 639.8 g/mol
- CAS number: 736992-21-5
- Form: Lyophilised powder
- Purity: >99% (HPLC)
- Storage: 2-8°C, dark, upright, do not freeze. Keep sealed until use.
Structure: an aromatic-cationic design
SS-31 is only four residues long, but each position was chosen deliberately. The sequence alternates aromatic and basic residues, a motif the Szeto-Schiller series used to combine cell permeability with mitochondrial targeting.
- D-Arginine at the N-terminus. The D-configuration makes the peptide less susceptible to many proteases than an all-L sequence.
- 2',6'-dimethyltyrosine (Dmt), a non-proteinogenic amino acid. The phenolic ring has been discussed in relation to the peptide's reported radical-scavenging chemistry.
- Lysine, contributing a second positive charge.
- Phenylalanine amide at the C-terminus. Amidation removes the negative charge of a free carboxyl group.
The net effect is a peptide carrying a 3+ charge at physiological pH, yet small and amphipathic enough to cross cell membranes in the experimental systems studied. Unlike many cationic compounds that accumulate in mitochondria because of the membrane potential, early work reported that SS-31 uptake was largely independent of membrane potential.
Cardiolipin: the proposed target
Cardiolipin is a phospholipid found almost exclusively in the inner mitochondrial membrane. It has four acyl chains and is closely associated with the protein complexes of the electron transport chain, including cytochrome c. Cardiolipin contributes to the folds (cristae) of the inner membrane and to the organisation of respiratory supercomplexes.
Work by Szeto and colleagues, including a 2013 study by Birk and colleagues in the Journal of the American Society of Nephrology, reported that SS-31 bound selectively to cardiolipin in model membranes and in isolated mitochondria. The authors proposed that this interaction affected how cytochrome c associated with cardiolipin, shifting it away from peroxidase activity and towards its electron-carrier role. Later biophysical studies examined how the peptide altered membrane surface charge and lipid packing. These remain mechanistic proposals drawn from in vitro and animal work.
Research history
Early 2000s: peptide antioxidants
The SS peptides were first described as cell-permeable compounds that reached the inner mitochondrial membrane. A 2004 paper by Zhao and colleagues in the Journal of Biological Chemistry reported that SS-31 and related peptides reduced markers of oxidative stress in cultured cells and isolated mitochondria.
Preclinical models
Over the following decade, SS-31 was investigated in rodent models of ischaemia-reperfusion, kidney injury, cardiac dysfunction and age-related changes in skeletal muscle. A review by Szeto in the British Journal of Pharmacology in 2014 summarised this body of preclinical work and the cardiolipin hypothesis.
Clinical development of elamipretide
Under the name elamipretide, the compound was taken into clinical development by Stealth BioTherapeutics. It has been evaluated in clinical trials in conditions including primary mitochondrial myopathy, Barth syndrome (a genetic disorder of cardiolipin remodelling) and heart failure. Outcomes varied between studies and indications. Readers should consult the relevant regulator for the current approval status of any elamipretide medicine. The SS-31 supplied by Compound Cave is a research chemical, not a medicine, and has no connection to any licensed product.
How SS-31 differs from other mitochondrial compounds
SS-31 is often mentioned alongside MOTS-c, but the two are very different. MOTS-c is a 16-residue peptide encoded in the mitochondrial genome and studied as a signalling molecule, whereas SS-31 is a synthetic tetrapeptide studied for its interaction with membrane lipids. Our MOTS-c pillar guide covers the mitochondrial-derived peptide family in detail.
SS-31 also differs from cofactor-focused approaches. Research on NAD+ and NMN concerns the supply of a redox cofactor, while SS-31 research concerns the physical environment of the respiratory chain. Other mitochondria-targeted compounds, such as MitoQ, use a lipophilic triphenylphosphonium cation that relies on membrane potential for accumulation, which is a different targeting strategy.
Laboratory handling notes
SS-31 is supplied as a lyophilised powder and, being a short peptide containing D-amino acids and a C-terminal amide, is chemically fairly robust in the dry state. Standard precautions still apply: store sealed at 2-8°C away from light, allow vials to equilibrate to room temperature before opening, and limit exposure to moisture. Commercial peptides are commonly supplied as salts (for example acetate or trifluoroacetate), so the net peptide content can differ from the gross weight. See how to store lyophilised peptides for more.
Identity is confirmed by mass spectrometry against the calculated molecular weight of 639.8 g/mol, and purity is specified at >99% by HPLC. Our guide to reading a peptide certificate of analysis explains both measurements.
View SS-31 in the catalogue.
Frequently asked questions
Is SS-31 the same as elamipretide?
Yes. SS-31 is the original research code for the tetrapeptide D-Arg-Dmt-Lys-Phe-NH2. Elamipretide is its international nonproprietary name, and it has also been known as MTP-131 and Bendavia.
What does Dmt mean in the SS-31 sequence?
Dmt is 2',6'-dimethyltyrosine, a modified tyrosine with two methyl groups on the aromatic ring. It is not one of the 20 standard amino acids.
What is cardiolipin?
Cardiolipin is a phospholipid found almost exclusively in the inner mitochondrial membrane. SS-31 has been reported in preclinical studies to bind selectively to cardiolipin.
Is the SS-31 sold by Compound Cave a medicine?
No. It is a research chemical supplied for laboratory research use only. It is not a medicine and is not for human or veterinary use.
How should SS-31 be stored?
Keep sealed vials at 2-8°C, in the dark and upright, and do not freeze. Keep the vial sealed until use.
References
- Zhao K, Zhao GM, Wu D, et al. (2004). Journal of Biological Chemistry, 279(33), 34682-34690. Cell-permeable SS peptides targeted to the inner mitochondrial membrane.
- Szeto HH. (2014). British Journal of Pharmacology, 171(8), 2029-2050. Review of SS-31 and cardiolipin.
- Birk AV, Liu S, Soong Y, et al. (2013). Journal of the American Society of Nephrology, 24(8), 1250-1261. SS-31 interaction with cardiolipin and cytochrome c.
- Szeto HH, Schiller PW. (2011). Pharmaceutical Research, 28(11), 2669-2679. Overview of the Szeto-Schiller peptide series.
SS-31 is a well-characterised tool compound for studying the inner mitochondrial membrane, with a clear chemical identity and a substantial preclinical literature.
For laboratory research use only. Not for human or veterinary use. See our research use only policy.