SS-31, known by the international non-proprietary name elamipretide and the development code MTP-131, is a four-residue aromatic-cationic peptide that concentrates in the inner mitochondrial membrane and binds cardiolipin. This SS-31 research peptide guide covers the Szeto–Schiller peptide chemistry, the cardiolipin and cytochrome c mechanism, what the clinical trial programme actually found, chemical specification and laboratory handling. Research context only.
Key takeaways
- SS-31 is H-D-Arg-Dmt-Lys-Phe-NH2 — a tetrapeptide with a D-amino acid, an unnatural residue (2′,6′-dimethyltyrosine) and a C-terminal amide.
- CAS 736992-21-5, formula C32H49N9O5, average molecular weight ≈639.8 Da.
- It belongs to the Szeto–Schiller (SS) series, whose defining feature is an alternating aromatic and cationic residue motif that allows cell penetration and mitochondrial accumulation.
- Uptake into the inner mitochondrial membrane is reported to be independent of membrane potential — unlike lipophilic cation approaches, so it still concentrates in depolarised mitochondria.
- The mechanism described by Szeto and Birk is cardiolipin binding: SS-31 modulates the cytochrome c–cardiolipin complex, suppressing its peroxidase activity while preserving electron-transport function and protecting cristae architecture.
- Unlike most research peptides, SS-31 has been through registrational clinical trials — and MMPOWER-3, the phase 3 study in primary mitochondrial myopathy, did not meet its primary endpoints.
- Two non-standard residues make identity confirmation by mass spectrometry particularly important on the certificate of analysis.
What is SS-31 (elamipretide)?
SS-31 is a synthetic tetrapeptide designed at Cornell by Hazel Szeto and Peter Schiller that crosses cell membranes, accumulates several hundred-fold in the inner mitochondrial membrane, and binds the mitochondria-specific phospholipid cardiolipin. It is the best-developed member of the Szeto–Schiller peptide series.
The compound carries several names in the literature and it pays to know all of them. SS-31 is the original laboratory designation. Elamipretide is the international non-proprietary name assigned when it entered clinical development. MTP-131 is a development code used in trial documentation. All three refer to the same molecule.
What sets SS-31 apart from most peptides in a research catalogue is its development history. It progressed through a full pharmaceutical programme including phase 3 trials in rare mitochondrial disease — which means, unusually, that there is genuine controlled human data to weigh, rather than only preclinical work.
This guide is aimed at researchers working on mitochondrial bioenergetics, ischaemia-reperfusion models or cardiolipin biology, and at purchasing staff who need verifiable specifications. It is not a protocol for administration to any organism.
Structure, sequence and chemical specification
SS-31 is H-D-Arg-Dmt-Lys-Phe-NH2: four residues, of which two are non-standard, plus a C-terminal amide. That is a great deal of engineering packed into a very short peptide, and each modification has a purpose.
The three modifications
Position 1 is D-arginine, the mirror-image stereoisomer of the natural L form. D-amino acids resist cleavage by mammalian proteases, which extends the peptide’s usable lifetime in biological media.
Position 2 is 2′,6′-dimethyltyrosine (Dmt), an unnatural tyrosine analogue with two methyl groups on the aromatic ring. It supplies the bulky aromatic character central to the SS-series design.
The C-terminus is amidated rather than left as a free carboxylate. Amidation removes a negative charge, raises the net positive charge and blocks carboxypeptidase attack from that end.
| Property | Value |
|---|---|
| Synonyms | Elamipretide (INN), MTP-131, SS-31 |
| Sequence | H-D-Arg-Dmt-Lys-Phe-NH2 |
| Residues | 4 |
| CAS number | 736992-21-5 |
| Molecular formula | C32H49N9O5 |
| Average molecular weight | ≈639.8 g/mol (free base) |
| Non-standard features | D-arginine at position 1; 2′,6′-dimethyltyrosine at position 2; C-terminal amide |
| Dmt full name | 2′,6′-dimethyl-L-tyrosine |
| Net charge at pH 7 | +3 |
| Molecular target described | Cardiolipin in the inner mitochondrial membrane |
| Appearance as supplied | White to off-white lyophilised powder |
| Typical QC methods | RP-HPLC purity, ESI-MS identity, chiral confirmation of D-Arg where specified |
The Szeto–Schiller design: why the aromatic-cationic motif matters
The Szeto–Schiller peptides share a design rule: alternating aromatic and cationic residues, which together produce a molecule that crosses membranes readily and then concentrates in the inner mitochondrial membrane. SS-31 is the series member that reached clinical development.
The most important consequence of that design is a mechanistic one. Many mitochondria-targeting strategies rely on lipophilic cations that accumulate because the mitochondrial matrix is electrically negative. That works only while the membrane potential holds — precisely the condition that fails in damaged mitochondria.
SS-31’s uptake into the inner membrane is reported to be independent of membrane potential. In a research setting that matters: the peptide should still partition into mitochondria in ischaemic or depolarised preparations, where potential-driven agents would not.
A second consequence is a practical one. Because the peptide accumulates into a membrane compartment, effective local concentration can be far higher than the nominal concentration in the medium. Reported concentration figures in the literature should be read with that in mind.
Cardiolipin, cytochrome c and the mechanism of action
The mechanism described across Szeto and Birk’s work is binding to cardiolipin — the four-tailed phospholipid found almost exclusively in the inner mitochondrial membrane — and thereby modulating the cytochrome c–cardiolipin complex. This is where the compound’s activity is thought to originate.
Why cardiolipin is the target
Cardiolipin is structurally unusual: two phosphatidyl groups joined by a glycerol bridge, giving four acyl chains and a compact anionic head group. It is enriched in cristae membranes, where it organises the respiratory chain complexes and their supercomplexes, and it anchors cytochrome c to the membrane.
The peroxidase problem
When cytochrome c binds cardiolipin in a particular conformation, it acquires peroxidase activity — it starts oxidising the very lipid it is bound to. Peroxidised cardiolipin releases cytochrome c, disrupts cristae architecture and impairs electron transport, which is a self-amplifying failure loop in ischaemia and other stresses.
Birk and colleagues reported in 2013 in the Journal of the American Society of Nephrology that SS-31 interacts with cardiolipin, protects cristae membranes, accelerates ATP recovery after ischaemia and mitigates acute kidney injury in their model. A companion 2014 paper in the British Journal of Pharmacology examined the cytochrome c–cardiolipin complex specifically, describing effects on electron transport and ATP synthesis.
Szeto’s own 2014 British Journal of Pharmacology review framed the compound as a first-in-class cardiolipin-protective agent — a mechanism class rather than a target-inhibition pharmacology.
What the preclinical research reports
The preclinical literature for SS-31 is unusually consistent for a research peptide, and it clusters around models where mitochondrial energy failure is the proximate problem: ischaemia-reperfusion, acute kidney injury and cardiac dysfunction.
The renal work is the best-documented strand. Birk and colleagues reported that SS-31 protected cristae membranes during ischaemia, allowed prompt ATP recovery on reperfusion and mitigated renal dysfunction. Follow-up work in the same field examined endothelial mitochondria and reported effects on microvascular rarefaction, inflammation and fibrosis in a renal ischaemia model.
The mechanistic literature broadened after 2020, when proteomic work mapped SS-31’s mitochondrial protein interaction landscape, indicating the peptide’s effects extend beyond a single lipid-binding event to the organisation of respiratory-chain proteins.
The clinical trial programme and what it found
Elamipretide is one of very few compounds in the research-peptide catalogue with published, randomised, controlled human trial data — and the headline result of the pivotal trial was negative. Reporting that honestly is more useful than quoting the mechanism alone.
MMPOWER-3 was a randomised trial of elamipretide in adults with primary mitochondrial myopathy. Karaa and colleagues published the results in Neurology in 2023. The trial did not meet its primary endpoints, which assessed change in the six-minute walk test and in fatigue across the total study population.
A 2024 post hoc analysis in the Orphanet Journal of Rare Diseases examined whether responses differed by genotype, reporting differential effects between genetic subgroups within the trial cohort. Post hoc subgroup findings are hypothesis-generating, not confirmatory, and should be described that way.
An earlier randomised crossover study in the same indication had reported more encouraging signals, which is a familiar pattern: promising early-phase results that a larger controlled trial does not confirm.
| Finding | Model | Source | Strength |
|---|---|---|---|
| Binds cardiolipin; protects cristae; speeds ATP recovery after ischaemia | Rodent renal ischaemia-reperfusion | J Am Soc Nephrol 2013 | Strong preclinical |
| Targets cytochrome c–cardiolipin complex to promote electron transport | Isolated mitochondria, biochemistry | Br J Pharmacol 2014 | Strong mechanistic |
| Described as first-in-class cardiolipin-protective compound | Review of the series | Br J Pharmacol 2014 | Review |
| Primary endpoints in primary mitochondrial myopathy | Randomised phase 3, humans | Neurology 2023 | Not met |
| Differential response by genotype subgroup | Post hoc analysis of the same trial | Orphanet J Rare Dis 2024 | Hypothesis-generating |
| Broader mitochondrial protein interactions | Proteomics | Published 2020 | Mechanistic, exploratory |
Laboratory handling, solution preparation and storage
SS-31 is chemically more robust than most peptides of its size — no methionine, no cysteine, no tryptophan, and a D-residue plus C-terminal amide that resist proteolysis — but it is still a lyophilised peptide and should be handled as one.
- Warm the vial before opening. Allow the sealed vial to reach room temperature so moisture does not condense onto the cold cake.
- Choose a diluent. The peptide is cationic and water-soluble. Sterile water suits single-use assay solutions; bacteriostatic water with 0.9% benzyl alcohol is used where a multi-draw stock is required.
- Add gently. Direct the diluent down the vial wall and swirl until dissolved. Avoid vortexing.
- Mind the plastics. Cationic peptides can adsorb to plastic surfaces at low concentrations; low-binding tubes and tips reduce losses in dilute working solutions.
- Aliquot and freeze. Split into single-use volumes so no aliquot is thawed twice.
- Record the batch. Log compound, batch, concentration, diluent and date against the certificate of analysis.
| Peptide mass in vial | Diluent added | Resulting concentration | Amount per 0.1 mL | Approx. molar concentration |
|---|---|---|---|---|
| 10 mg | 1 mL | 10 mg/mL | 1000 mcg | ≈15.6 mM |
| 10 mg | 2 mL | 5 mg/mL | 500 mcg | ≈7.8 mM |
| 10 mg | 5 mL | 2 mg/mL | 200 mcg | ≈3.1 mM |
| 20 mg | 2 mL | 10 mg/mL | 1000 mcg | ≈15.6 mM |
| 20 mg | 4 mL | 5 mg/mL | 500 mcg | ≈7.8 mM |
| 50 mg | 10 mL | 5 mg/mL | 500 mcg | ≈7.8 mM |
Molar figures use the free-base molecular weight of 639.8 Da and ignore counter-ion salt and residual water, so they are upper bounds. Because SS-31 partitions into membranes, effective concentration at the inner mitochondrial membrane in a cell assay is not the same as bulk medium concentration — an important caveat when comparing published figures. Fuller method detail is in the reconstitution guide.
SS-31 compared with other mitochondrial research peptides
SS-31 and MOTS-c are both called mitochondrial peptides, but they occupy opposite ends of the biology: SS-31 is a synthetic membrane-targeting agent, MOTS-c is an endogenous signalling peptide encoded by mitochondrial DNA.
SS-31 — structural / membrane
Fully synthetic, designed rather than discovered. Acts physically at the inner membrane by binding cardiolipin. Effects are on organelle integrity and bioenergetic recovery. Has controlled human trial data, with a negative pivotal result.
MOTS-c — signalling
Endogenous, encoded in the mitochondrial 12S rRNA gene. Acts through metabolite flux and AMPK, and translocates to the nucleus to alter gene expression. Human data is observational; no large interventional trial.
For experimental design this distinction is decisive. A study of cristae morphology or ATP recovery after ischaemia points toward SS-31. A study of AMPK signalling, metabolic gene expression or exercise biology points toward MOTS-c. They are not substitutes for each other.
SS-31 in the GenoPept store
Frequently asked questions
Is SS-31 the same as elamipretide?
Yes. SS-31 is the original Szeto–Schiller laboratory designation, elamipretide is the international non-proprietary name assigned for clinical development, and MTP-131 is a development code used in trial documentation. All three refer to the same tetrapeptide, H-D-Arg-Dmt-Lys-Phe-NH2, CAS 736992-21-5.
What is the sequence of SS-31?
SS-31 is H-D-Arg-Dmt-Lys-Phe-NH2: D-arginine, 2′,6′-dimethyltyrosine, lysine and phenylalanine with an amidated C-terminus. Two of the four residues are non-standard, which is why mass-spectrometric identity confirmation matters more here than for an all-natural peptide of the same length.
What is Dmt in SS-31?
Dmt is 2′,6′-dimethyl-L-tyrosine, an unnatural amino acid in which two methyl groups are added to the tyrosine aromatic ring. It provides the bulky aromatic character that, alternating with the cationic residues, defines the Szeto–Schiller peptide series and drives partitioning into the inner mitochondrial membrane.
How does SS-31 target mitochondria?
Through its alternating aromatic-cationic structure, which lets it cross membranes and concentrate in the inner mitochondrial membrane where it binds cardiolipin. Notably, this accumulation is reported to be independent of membrane potential, so unlike lipophilic-cation approaches it should still partition into depolarised or damaged mitochondria.
What is cardiolipin and why does it matter here?
Cardiolipin is a four-tailed phospholipid found almost exclusively in the inner mitochondrial membrane, where it organises respiratory chain complexes and anchors cytochrome c. When the cytochrome c–cardiolipin complex gains peroxidase activity it oxidises cardiolipin, disrupting cristae and impairing electron transport. SS-31 is described as modulating that interaction.
Did elamipretide succeed in clinical trials?
Not in its pivotal study. MMPOWER-3, the randomised phase 3 trial in adults with primary mitochondrial myopathy, did not meet its primary endpoints for six-minute walk test and fatigue across the total population, as published in Neurology in 2023. A 2024 post hoc analysis reported differences between genotype subgroups, which is hypothesis-generating rather than confirmatory.
How should SS-31 be stored?
Sealed lyophilised material should be kept frozen at −20 °C for long-term storage, with 2–8 °C acceptable as a working store, dry and dark. Reconstituted solutions should be refrigerated and used promptly, or aliquoted into single-use volumes and frozen. SS-31 contains no methionine, cysteine or tryptophan, so it is less oxidation-prone than many peptides.
How does SS-31 differ from MOTS-c?
They work on different principles. SS-31 is a fully synthetic peptide that acts physically at the inner mitochondrial membrane by binding cardiolipin, affecting organelle integrity and bioenergetic recovery. MOTS-c is an endogenous peptide encoded in mitochondrial DNA that signals through metabolite flux, AMPK and nuclear gene expression. They are not interchangeable in experimental design.
References
- Szeto HH. First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics. British Journal of Pharmacology. 2014;171(8):2029–2050. DOI
- Birk AV, Liu S, Soong Y, et al. The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin. Journal of the American Society of Nephrology. 2013;24(8):1250–1261. DOI
- Birk AV, Chao WM, Bracken C, Warren JD, Szeto HH. Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis. British Journal of Pharmacology. 2014;171(8):2017–2028.
- Karaa A, Bertini E, Carelli V, et al. Efficacy and safety of elamipretide in individuals with primary mitochondrial myopathy: the MMPOWER-3 randomized clinical trial. Neurology. 2023;101(3):e238–e252. DOI
- Karaa A, et al. Genotype-specific effects of elamipretide in patients with primary mitochondrial myopathy: a post hoc analysis of the MMPOWER-3 trial. Orphanet Journal of Rare Diseases. 2024;19:431. DOI
Research-grade SS-31, batch-verified
GenoPept supplies SS-31 (elamipretide) as lyophilised vials with a per-batch third-party certificate of analysis covering HPLC purity and mass-spectrometry identity against the 639.8 Da target mass, dispatched from the UK, strictly for laboratory research.