SS-31 is a synthetic tetrapeptide, D-Arg-Dmt-Lys-Phe-NH2, that crosses cell membranes and concentrates on the inner mitochondrial membrane, where it binds the phospholipid cardiolipin. It was designed by Hazel Szeto and Peter Schiller and is also known as elamipretide, MTP-131 and Bendavia. On September 19, 2025, the FDA granted accelerated approval to elamipretide, as Forzinity, for Barth syndrome, making SS-31 one of the few research peptides that is also the active ingredient of an approved drug.
This profile covers the molecule itself: its identity and unusual residues, where the Szeto-Schiller peptides came from, what the literature says about cardiolipin binding, the models it has been studied in, and the exact scope of the 2025 approval. It ends with the practical points that apply when SS-31 is handled as a lyophilized research reagent.
Identity at a glance
The free-base values below are from PubChem (CID 11764719). The salt values are from the FDA prescribing information for Forzinity, which describes the drug substance as a hydrochloride salt.
| Property | Value |
|---|---|
| Names | SS-31, elamipretide, MTP-131, Bendavia |
| Sequence | D-Arg-Dmt-Lys-Phe-NH2 (Dmt = 2′,6′-dimethyl-L-tyrosine) |
| Length | 4 residues, linear, C-terminal amide |
| Molecular formula (free base) | C32H49N9O5 |
| Molecular weight (free base) | 639.8 g/mol |
| Hydrochloride salt (FDA label) | C32H49N9O5 · 3HCl, 749.2 g/mol |
| CAS number | 736992-21-5 |
| PubChem CID | 11764719 |
| UNII | 87GWG91S09 |
| Solubility | The hydrochloride salt is described by FDA as freely soluble in water |
Three features of the sequence stand out.
- A D-amino acid at the N-terminus. The first residue is D-arginine, not the L-form found in proteins. D-residues are poor substrates for most peptidases, which helps explain why such a short peptide is stable enough to study in cells and animals.
- A non-proteinogenic tyrosine. Dmt carries two methyl groups on the aromatic ring next to the phenol. It is a residue borrowed from opioid peptide chemistry, and in SS-31 it contributes the radical-scavenging behavior described below.
- An amidated C-terminus. Replacing the terminal carboxylate with an amide removes a negative charge. With the free N-terminal amine, the arginine guanidinium and the lysine amine all protonated at neutral pH, the peptide carries a net charge of +3.
The outcome is a short molecule that alternates aromatic and basic residues: basic, aromatic, basic, aromatic. That pattern is the defining feature of the whole Szeto-Schiller series.
Where the Szeto-Schiller peptides came from
The SS peptides grew out of opioid peptide research. Szeto and Schiller were studying small Dmt-containing tetrapeptides when they found that some of these aromatic-cationic molecules entered cells readily and accumulated in mitochondria, a finding Szeto later described as a chance discovery. Earlier members of the series, such as SS-02 and SS-20, were characterized alongside SS-31 before SS-31 became the lead compound.
The foundational paper is Zhao and colleagues in 2004. Working with neuronal N2A cells and isolated mitochondria, they reported that these peptides are cell-permeable, concentrate about 1,000-fold in the inner mitochondrial membrane, reduce intracellular reactive oxygen species, and inhibit the mitochondrial permeability transition and swelling. A control experiment was telling: analogs lacking Dmt did not reduce mitochondrial reactive oxygen species or swelling, pointing to that residue as the source of the scavenging activity.
The code MTP-131 came with commercial development, and Bendavia was the name used when SS-31 entered Phase 2 trials with its developer, then called Stealth Peptides. Elamipretide is the International Nonproprietary Name.
Mechanism: cardiolipin, not a receptor
SS-31 does not act on a cell-surface receptor. Its proposed target is a lipid.
Cardiolipin is a phospholipid found almost exclusively in the inner mitochondrial membrane. It has four acyl chains and two phosphate groups, which gives it a cone shape and a strong negative charge, and it is needed for the tight curvature of the cristae and for the assembly of the respiratory chain complexes. It also binds cytochrome c. When cardiolipin is oxidized or when cytochrome c is displaced, the cytochrome c-cardiolipin complex can act as a peroxidase and oxidize cardiolipin further.
Birk and colleagues (2013) used a fluorescent analog of SS-31 to show that the peptide binds cardiolipin with high affinity. They also reported that the SS-31-cardiolipin complex inhibited the peroxidase activity of cytochrome c by protecting its heme iron. The proposed binding mode combines electrostatics, between the peptide's three positive charges and cardiolipin's phosphate head groups, with hydrophobic insertion of the aromatic Dmt and Phe side chains among the acyl chains. Szeto's later reviews add that uptake into mitochondria does not depend on the membrane potential, which separates SS-31 from lipophilic cation probes that require a polarized membrane.
The FDA label sums up the same idea in one line, describing elamipretide as a mitochondrial cardiolipin binder that localizes to the inner mitochondrial membrane.
This mechanism links directly to the one approved indication. Barth syndrome is an X-linked disorder caused by variants in TAFAZZIN, the gene for tafazzin, an acyltransferase that remodels newly made cardiolipin. UniProt's record for tafazzin describes it as required for the tissue-specific acyl chain composition of cardiolipin. A compound that binds cardiolipin is therefore a mechanistically obvious candidate for a cardiolipin remodeling disorder.
Research models
The preclinical literature on SS-31 is large, and it is spread across tissues with high mitochondrial demand. Reviews by Szeto summarize work in:
- Cell systems. Neuronal N2A cells, endothelial cells, cardiomyocytes and isolated mitochondria.
- Heart. Isolated perfused guinea pig hearts, and coronary artery ligation models in rats, rabbits and sheep, along with models of cardiac hypertrophy and heart failure.
- Kidney. Renal ischemia-reperfusion models in rats and pigs. In the Birk study, pretreating rats with SS-31 preserved cristae membranes during renal ischemia and prevented mitochondrial swelling.
- Brain and nerve. Cerebral ischemia in mice and models of Parkinson's disease and amyotrophic lateral sclerosis.
- Skeletal muscle. Atrophy models induced by immobilization or mechanical ventilation.
The common thread is mitochondrial stress, particularly ischemia followed by reperfusion, where cristae structure and cytochrome c handling are disturbed. For a peptide with a very different origin that is also discussed in mitochondrial research, see the profile of MOTS-c, which is encoded in the mitochondrial genome rather than designed in a laboratory.
Human trials and the 2025 approval
Elamipretide has been through a long series of registered human trials. Listed on ClinicalTrials.gov, they include a Phase 2a trial in patients undergoing coronary intervention for ST-elevation myocardial infarction (EMBRACE, NCT01572909), Phase 2 trials in heart failure, a Phase 3 trial in primary mitochondrial myopathy (MMPOWER-3, NCT03323749), which the registry lists as terminated after its double-blind part did not meet its primary endpoints, a Phase 3 trial in primary mitochondrial disease (NuPower, NCT05162768), a Phase 3 trial in dry age-related macular degeneration (ReNEW, NCT06373731), and a Phase 2/3 crossover trial in Barth syndrome (TAZPOWER, NCT03098797).
The regulatory facts are precise and worth stating exactly:
- Approval. On September 19, 2025, FDA approved Forzinity (elamipretide) injection under NDA 215244, held by Stealth BioTherapeutics.
- Indication. The approved use is to improve muscle strength in adult and pediatric patients with Barth syndrome weighing at least 30 kg.
- Pathway. It is an accelerated approval under section 506(c) of the Federal Food, Drug, and Cosmetic Act and 21 CFR 314.510. Accelerated approval rests on an intermediate endpoint, here knee extensor muscle strength, and continued approval depends on a confirmatory trial.
- Confirmatory trial. A Phase 3b/4 trial in Barth syndrome, 4TAZPower (NCT07531251), is listed on ClinicalTrials.gov as recruiting as of September 2026.
- Other status. The approval letter also granted a rare pediatric disease priority review voucher. No other indication is approved.
Two consequences follow for a laboratory. Elamipretide is now a characterized drug substance with an FDA label that documents its salt form, formula and mechanism, which is useful reference data. And research-grade SS-31 is not Forzinity: it is a chemical reagent made to a research specification, not a finished drug product, and it is supplied only for in-vitro and laboratory research.
Handling SS-31 in the lab
- Salt form. The drug substance is a trihydrochloride. Research material may be supplied as a different salt, commonly acetate or trifluoroacetate, which changes the formula weight and therefore the calculation from net content to molar concentration. Check the certificate of analysis for the stated form before making stock solutions.
- Solvent. The peptide is small and highly charged, and it dissolves readily in water. Sterile water or a simple aqueous buffer is the usual starting point for in-vitro stocks.
- Stability. The D-arginine and the C-terminal amide protect against exopeptidases, but the Dmt phenol can still oxidize, so protect solutions from light and avoid repeated freeze-thaw. The posts on how lyophilization works and how to store peptides cover the general rules.
- Analytics. With a free-base mass of 639.8 Da, SS-31 is easy to confirm by mass spectrometry, typically as the [M+H]⁺ or multiply charged ions given its three basic sites. HPLC purity is reported as the area of the principal peak relative to total signal, as described in the post on peptide purity.
Anhydrolabs supplies SS-31 as a lyophilized powder in vacuum-sealed vials, with each lot's certificate on the product page, and also as 10-vial kits.
