SS-31 Research, Specifications & Scientific Information

Introduction

SS-31 is the laboratory name for a four-residue peptide that has since been through an entire pharmaceutical development programme under three further names — MTP-131, Bendavia, and finally elamipretide. It is the most extensively studied compound in this library that is not an incretin, and its record is unusually informative because it contains both a clear negative result in its largest trial and an approval granted from its smallest.

What distinguishes it chemically is that it does not act at a receptor. Its target is cardiolipin, a phospholipid found almost exclusively in the inner mitochondrial membrane, identified by using a polarity-sensitive fluorescent analogue of the peptide itself ^[1]. The consequences described are architectural — preservation of cristae structure — rather than catalytic.

The clinical programme ran in three directions. A phase 3 trial in primary mitochondrial myopathy randomised 218 participants and missed both primary endpoints, with the publication classifying the result as Class I evidence of no effect ^[7]. A phase 2 trial in geographic atrophy also missed its primary endpoints ^[10]. And a twelve-participant trial in Barth syndrome, through its open-label extension, produced the data on which an accelerated approval was granted in September 2025 ^[8].

What Is SS-31?

SS-31 is a synthetic tetrapeptide with the sequence D-Arg-Dmt-Lys-Phe-NH2. It belongs to the Szeto-Schiller series of mitochondria-targeted aromatic-cationic peptides, developed at Weill Cornell, and it is the member of that series that reached clinical development.

Three of its structural features are deliberate departures from ordinary peptide chemistry. Position 1 is D-arginine rather than the L form. Position 2 is 2,6-dimethyltyrosine, a non-proteinogenic residue carrying two methyl groups on the aromatic ring. The C-terminus is a primary amide rather than a free carboxylic acid. Together these make the molecule resistant to peptidases and give it the alternating aromatic-cationic pattern the series is named for.

Its regulatory position is specific and should be read exactly. A finished pharmaceutical product containing this peptide — FORZINITY, elamipretide hydrochloride injection, NDA 215244, sponsored by Stealth BioTherapeutics — received accelerated approval from the U.S. Food and Drug Administration on 19 September 2025, with priority review and orphan designation, for one rare genetic condition. That approval covers one manufacturer, one finished product, one indication and one population. It is granted on an intermediate clinical endpoint, and continued approval may be contingent on verification and description of clinical benefit in a confirmatory trial.

None of that extends to research-grade material supplied for laboratory use, which is a different substance in a different form made to a different standard.

SS-31 Specifications

This sequence cannot be written in single-letter code, and the reason matters. Position 1 is D-arginine rather than the L form, and position 2 is 2,6-dimethyltyrosine (Dmt), a non-proteinogenic residue with two methyl groups on the aromatic ring; the C-terminus is a primary amide rather than a free acid. All other residues are L. Those three departures from ordinary peptide chemistry are what give the molecule its alternating aromatic-cationic character and its resistance to peptidases. The formula and mass here are for the free base, as recorded by PubChem (CID 11764719) with CAS registry number 736992-21-5 and FDA/NCATS UNII code 87GWG91S09. The approved pharmaceutical product is the trihydrochloride salt: the FDA label for FORZINITY records elamipretide hydrochloride as C32H49N9O5·3HCl with a molecular weight of 749.2, which is a different number for the same peptide in a different salt form. A catalogue figure and a certificate of analysis are not interchangeable, and with a salt-form difference of more than 100 daltons that is not a fine distinction. Any figure on this page is a reference value: the certificate of analysis supplied with a laboratory order is the record for a given lot.

Values that a public register does not carry are shown as not publicly characterised rather than estimated. Identifiers are reference values; the certificate of analysis supplied with a laboratory order is the record for a given lot.

How Does SS-31 Work?

The mechanism is unusual enough to be worth stating slowly, because almost every peptide in this library acts at a receptor and this one does not.

Cardiolipin is a four-tailed anionic phospholipid found almost exclusively in the inner mitochondrial membrane. It is required for the formation of cristae — the folds that carry the respiratory chain — and it binds cytochrome c. When cardiolipin is peroxidised, cristae architecture is lost and ATP synthesis fails. That chain of events is the common final pathway of a great many forms of mitochondrial dysfunction, which is why a molecule that intervenes in it has been tested across conditions with little else in common.

SS-31 binds cardiolipin with high affinity and concentrates in the inner mitochondrial membrane as a result ^[1]. Two consequences are described. The first is structural: cristae membranes are protected and mitochondrial swelling prevented. The second is enzymatic in a protective direction: the complex formed between the peptide and cardiolipin inhibits the peroxidase activity of cytochrome c — the activity that catalyses cardiolipin peroxidation — by protecting its heme iron ^[1].

Later biophysical work refined this. Binding to lipid bilayers and modulation of membrane surface electrostatics is described as a key component of the mechanism rather than a side effect of it ^[4], and a structure-activity study across the tetrapeptide series related specific residue changes to specific membrane effects ^[5].

The approved label compresses all of this into one sentence: a mitochondrial cardiolipin binder that localises to the inner mitochondrial membrane and improves mitochondrial morphology and function. That is the regulator's summary, and it is notably modest about what follows from it.

SS-31 Mechanism of Action

In vitro research

Identification of the target. A polarity-sensitive fluorescent analogue of the peptide was used to demonstrate high-affinity binding to cardiolipin. The peptide–cardiolipin complex inhibited cytochrome c peroxidase activity, the activity responsible for cardiolipin peroxidation and consequent mitochondrial damage during ischaemia, by protecting the heme iron ^[1].

This is the foundational result for the whole programme, and its design deserves note: the binding partner was found by making a reporter version of the drug rather than by screening a target library, which is why the answer came back as a lipid rather than as a protein.

Membrane biophysics. The peptide binds lipid bilayers and modulates their surface electrostatics, and that modulation is described as a key component of its mechanism of action rather than as an incidental property ^[4]. A subsequent study across a series of mitochondria-targeted tetrapeptides related structural variation within the series to differences in membrane interaction, establishing structure-activity relationships for the class ^[5].

The framing review. The class was described in 2014 as the first cardiolipin-protective compound proposed as a therapeutic agent to restore mitochondrial bioenergetics ^[2]. That review is the clearest statement of the hypothesis the later clinical programme tested — and, read against the phase 3 result described below, it is also a useful illustration of how far a well-supported molecular mechanism can be from a clinical effect.

Findings in this section were obtained in cell-free systems, in isolated mitochondria and in model membranes. Nothing in them establishes anything about intact animals or about humans.

What Is SS-31 Being Researched For?

• Barth syndrome — a phase 2/3 randomised crossover trial in 12 participants followed by a 168-week open-label extension, the basis of the accelerated approval ^{[8, 11]}, with a separate natural-history comparison study ^[6].
• Primary mitochondrial myopathy — a phase 2 crossover trial in 30 participants ^{[3, 12]} followed by a phase 3 trial in 218 ^{[7, 13]} and a genotype-stratified post hoc analysis ^[9].
• Dry age-related macular degeneration with non-central geographic atrophy — a phase 2 randomised placebo-controlled trial in 176 participants ^{[10, 14]}.
• Renal ischaemia and reperfusion — rat work reported alongside the identification of the binding target ^[1].
• Cardiolipin and membrane biophysics — the in vitro and structure-activity literature ^{[4, 5]}.

Each of those is research into a pharmaceutical product candidate, conducted by or for its sponsor under a registered protocol. None of it is research into, or evidence about, research-grade material supplied for laboratory use.

Human Research on SS-31

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

Phase 2 crossover in primary mitochondrial myopathy (MMPOWER-2)

Population. 30 participants with genetically confirmed primary mitochondrial myopathy, randomised 1:1 to four weeks of 40 mg daily subcutaneous elamipretide then four weeks of placebo, or the reverse, separated by a four-week washout ^{[3, 12]}.

Endpoint and duration. Primary endpoint the distance walked on the six-minute walk test; secondary endpoints patient-reported fatigue instruments and functional assessments ^[3].

Result. Six-minute walk distance was 398.3 ± 134.16 m on the peptide against 378.5 ± 125.10 m on placebo — a difference of 19.8 m (95% CI −2.8 to 42.5; p = 0.0833), which did not reach significance. Patient-reported measures did: total fatigue and total fatigue during activities on the symptom assessment (p = 0.0006 and p = 0.0018), the Neuro-QoL Fatigue Short Form (p = 0.0115) and the Patient Global Assessment (p = 0.0421). The Physician Global Assessment (p = 0.0636), Triple Timed Up and Go (p = 0.8423) and wrist and hip accelerometry (p = 0.9345, p = 0.7326) showed no change ^[3].

Adverse events. Injection-site reactions in 80% of participants, mostly mild. No serious adverse events and no deaths ^[3].

Limitations. Thirty participants over four weeks per period. The primary endpoint was missed; the significant findings are patient-reported and the objective functional measures — accelerometry, timed movement — were flat. The authors describe the result as an efficacy signal supporting a phase 3 trial.

Phase 3 in primary mitochondrial myopathy (MMPOWER-3)

Population. 218 participants with genetically confirmed primary mitochondrial myopathy, randomised 1:1 to 24 weeks of 40 mg daily subcutaneous elamipretide or placebo. Mean age 45.6 years, 64% women, 94% White; 162 (74%) carried a mitochondrial DNA alteration and the remainder nuclear DNA defects ^{[7, 13]}.

Endpoint and duration. Co-primary endpoints: change from baseline to week 24 in six-minute walk distance, and total fatigue on the Primary Mitochondrial Myopathy Symptom Assessment. Baseline six-minute walk distance was 336.7 ± 81.2 m ^[7].

Result. The trial did not meet either primary endpoint. The difference in least-squares mean change against placebo was −3.2 m on the six-minute walk test (95% CI −18.7 to 12.3; p = 0.69) and −0.07 on the total fatigue score (95% CI −0.10 to 0.26; p = 0.37). The publication classifies this as Class I evidence that the compound does not improve those endpoints at 24 weeks. Tolerability was good, most adverse events being mild to moderate ^[7].

Limitations and significance. This is the largest and most rigorous trial of the compound, it was adequately powered, and it was negative on both primary endpoints. A genotype-stratified post hoc analysis was published subsequently ^[9]; post hoc genotype subgrouping after a failed primary analysis generates hypotheses and does not rescue a result. The trial's registry record shows it as terminated.

Phase 2/3 crossover and 168-week extension in Barth syndrome (TAZPOWER)

Population. 12 participants aged 12 or over and weighing more than 30 kg with genetically confirmed Barth syndrome, in a randomised double-blind placebo-controlled crossover trial; 10 entered the 168-week open-label extension and 8 reached week 168 ^{[8, 11]}.

Endpoint and duration. Randomised phase: 28 weeks, with primary endpoints six-minute walk distance and total fatigue on the Barth Syndrome Symptom Assessment. Extension: 168 weeks, with safety and tolerability as primary endpoints ^[8].

Result in the randomised phase. The compound was not superior to placebo on either primary endpoint. Knee extensor muscle strength, measured by handheld dynamometry, was a secondary endpoint; the approved label records median change at week 12 of −5 newtons on placebo and +4 newtons on elamipretide, from a median baseline of 124 newtons.

Result in the open-label extension. Increases in knee extensor muscle strength that were absent in the randomised phase appeared in the extension: median change from pre-treatment baseline of +34 newtons at week 12, +68 at week 24, +57 at week 36, +41 at week 48, +35 at week 72 and +63 at week 168. Six-minute walk distance improved significantly at all extension time points, cumulatively 96.1 m by week 168 (p = 0.003). Total fatigue scores were below baseline at all extension time points. Three-dimensional left ventricular stroke, end-diastolic and end-systolic volumes improved, and the monolysocardiolipin to cardiolipin ratio — the biochemical signature of the underlying genetic defect — moved in the expected direction ^[8].

Limitations, and why they matter here. Ten participants, open-label, single-arm, no concurrent control. Improvements that were absent under blinded placebo-controlled conditions and appeared only after unblinding are exactly the pattern that open-label extensions are known to produce. A separate natural-history comparison study was conducted to address that gap by providing an external control ^[6]. The regulator's own position is recorded on the label: the approval is accelerated, based on knee extensor muscle strength as an intermediate clinical endpoint, and continued approval may be contingent on verification and description of clinical benefit in a confirmatory trial.

Preclinical Research on SS-31

Animal research

The animal work that accompanied the identification of the binding target remains the clearest demonstration of what the compound does in an intact organism.

Ischaemia depletes ATP and destroys the cristae membranes on which mitochondrial ATP synthesis depends, so ATP restoration after reperfusion is delayed. Pre-treatment of rats with SS-31 protected cristae membranes during renal ischaemia and prevented mitochondrial swelling. Prompt restoration of ATP on reperfusion was followed by rapid repair of ATP-dependent processes — restoration of the actin cytoskeleton and of cell polarity — together with inhibition of apoptosis, protection of tubular barrier function, and mitigation of renal dysfunction ^[1].

The structure of that argument is worth noticing: a molecular binding event, a structural consequence, a bioenergetic consequence, and then a functional one, each measured. It is a well-built preclinical case, and it is the case that the phase 3 trial in primary mitochondrial myopathy subsequently failed to translate. Both facts belong in any honest account of this compound.

Findings described in this section were observed in rats. Nothing in them establishes anything about humans.

Other Areas of SS-31 Research

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

The third clinical direction was ophthalmic, on the reasoning that photoreceptors and retinal pigment epithelium are among the most mitochondria-dense tissues in the body.

ReCLAIM-2. A prospective phase 2 randomised, placebo-controlled, double-masked multicentre trial in participants aged 55 or over with dry age-related macular degeneration and geographic atrophy. 176 were randomised, 117 to 40 mg daily subcutaneous elamipretide and 59 to placebo, for 48 weeks with four weeks of follow-up ^{[10, 14]}.

Primary endpoints, not met. Mean change from baseline in low-luminance best-corrected visual acuity, and change in square-root-converted geographic atrophy area on optical coherence tomography. Neither reached statistical significance ^[10].

Pre-specified additional endpoints. Progression of complete ellipsoid zone attenuation was reduced by 43% against placebo (nominal p = 0.0034) and progression of partial ellipsoid zone attenuation by 47% (nominal p = 0.0040) at week 48. More participants gained 10 or more letters of low-luminance acuity on the compound than on placebo, 14.6% against 2.1% (nominal p = 0.0404). Adverse events occurred in 86% of the treated group and 71% of placebo, injection-site reactions being the most common ^[10].

How to read this. The word "nominal" before each p-value is the authors' own, and it means the analysis was not part of the confirmatory hierarchy — these values are not corrected for multiplicity and do not carry the statistical weight of a met primary endpoint. The authors' argument is that ellipsoid zone attenuation is a surrogate for photoreceptor loss that precedes and predicts vision loss, and they state that this endpoint will serve as the primary endpoint in later development ^[10]. That is a reasonable scientific position and it is also, structurally, the same move as the Barth syndrome approval: a trial that missed its clinical endpoints, carried forward on a measure one step upstream of them.

Current Research Status

Status as of September 22, 2026. This block is rendered from maintained fields, not from prose, so it cannot go stale in one place and stay current in another.

SS-31 vs Related Compounds

Target class

SS-31 binds a membrane lipid, cardiolipin ^[1]. MOTS-c and humanin, the other mitochondrial peptides in this library, are mitochondria-derived peptides encoded in mitochondrial DNA and act as signalling molecules. Same organelle, opposite relationship to it: one is an exogenous molecule that goes to mitochondria, the others are endogenous molecules that come from them.

Within its own series

SS-31 is one of a series of Szeto-Schiller aromatic-cationic tetrapeptides; structure-activity relationships across that series have been published ^[5]. SS-31 is the member that reached clinical development, and results from it do not transfer to the others.

Free base versus salt

The identifiers on this page are for the free base, C32H49N9O5, 639.8 g/mol. The approved product is the trihydrochloride, C32H49N9O5·3HCl, 749.2. That is a difference of more than 100 daltons in nominal mass and a corresponding difference in peptide content by weight.

Names for the same molecule

SS-31 (laboratory), MTP-131 (development code), Bendavia (former product name), elamipretide (International Nonproprietary Name), FORZINITY (approved brand). Literature searches that use only one of these will miss most of the record.

Regulatory position

One accelerated approval in the United States, for a single rare indication in a single product, granted 19 September 2025 under NDA 215244. Approval is specific to a compound, a product, an indication and a jurisdiction, and it does not generalise — least of all to material supplied as a laboratory reagent.

No comparison of effect between these compounds is made on this page.

Chemical & Molecular Characteristics

SS-31 is a four-residue peptide that cannot be written in single-letter code. PubChem carries the free base as compound identifier 11764719, with CAS registry number 736992-21-5 and FDA/NCATS UNII code 87GWG91S09, molecular formula C32H49N9O5 and average mass 639.8 g/mol.

The D-arginine at position 1. Substituting the D enantiomer at the N-terminus blocks aminopeptidase cleavage, which is the commonest route by which a short peptide is destroyed in plasma. It also means that any analytical method insensitive to stereochemistry — mass spectrometry included — cannot distinguish the correct molecule from its all-L counterpart, which would be a different and far less stable compound of identical mass.

The 2,6-dimethyltyrosine at position 2. Dmt is not a proteinogenic residue and has no single-letter symbol. Its two ring methyl groups increase hydrophobicity and constrain the side-chain rotation of the aromatic ring, and the alternating aromatic-cationic pattern it completes is what the Szeto-Schiller series is named for. It is also a synthetically expensive residue, which is relevant to how a supplied material was actually made.

The C-terminal amide. Phenylalaninamide rather than free phenylalanine removes the terminal negative charge and blocks carboxypeptidase cleavage. Incomplete amidation leaves the free acid — a peptide one dalton heavier that is chromatographically similar and biologically different, and it is one of the specific impurities a certificate of analysis for this peptide should address.

Net charge. Two of four residues are basic, there is no acidic residue, and the C-terminus is neutral, so the molecule carries a substantial net positive charge at physiological pH. That charge is not incidental: it is part of how the peptide partitions into the inner mitochondrial membrane ^[4].

Salt form and mass. The approved product's label records the trihydrochloride at 749.2 against 639.8 for the free base. Three chloride counter-ions account for roughly 15% of the mass, so a milligram figure means substantially different amounts of peptide depending on which form is being weighed.

Analytical Specifications

Analytical figures are lot-specific. Fields the catalog does not carry for the current lot are omitted rather than filled with a typical value. The certificate of analysis and the safety data sheet for the exact lot supplied are provided with a laboratory order; no purity figure on this page is a substitute for that document.

Frequently Asked Questions

Scientific References

1. 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 : JASN; 2013. PMID 23813215 doi:10.1681/ASN.2012121216
2. Szeto HH. First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics British journal of pharmacology; 2014. PMID 24117165 doi:10.1111/bph.12461
3. Karaa A, Haas R, Goldstein A, et al.. A randomized crossover trial of elamipretide in adults with primary mitochondrial myopathy Journal of cachexia, sarcopenia and muscle; 2020. PMID 32096613 doi:10.1002/jcsm.12559
4. Mitchell W, Ng EA, Tamucci JD, et al.. The mitochondria-targeted peptide SS-31 binds lipid bilayers and modulates surface electrostatics as a key component of its mechanism of action The Journal of biological chemistry; 2020. PMID 32273339 doi:10.1074/jbc.RA119.012094
5. Mitchell W, Tamucci JD, Ng EL, et al.. Structure-activity relationships of mitochondria-targeted tetrapeptide pharmacological compounds eLife; 2022. PMID 35913044 doi:10.7554/eLife.75531
6. Hornby B, Thompson WR, Almuqbil M, et al.. Natural history comparison study to assess the efficacy of elamipretide in patients with Barth syndrome Orphanet journal of rare diseases; 2022. PMID 36056411 doi:10.1186/s13023-022-02469-5
7. 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. PMID 37268435
8. Thompson WR, Manuel R, Abbruscato A, et al.. Long-term efficacy and safety of elamipretide in patients with Barth syndrome: 168-week open-label extension results of TAZPOWER Genetics in medicine : official journal of the American College of Medical Genetics; 2024. PMID 38602181 doi:10.1016/j.gim.2024.101138
9. Karaa A, Bertini E, Carelli V, 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. PMID 39574155 doi:10.1186/s13023-024-03421-5
10. Ehlers JP, Hu A, Boyer D, et al.. ReCLAIM-2: A Randomized Phase II Clinical Trial Evaluating Elamipretide in Age-related Macular Degeneration, Geographic Atrophy Growth, Visual Function, and Ellipsoid Zone Preservation Ophthalmology science; 2025. PMID 39605874 doi:10.1016/j.xops.2024.100628
11. A Trial to Evaluate Safety, Tolerability and Efficacy of Elamipretide in Subjects With Barth Syndrome 2017. NCT03098797
12. Safety, Tolerability, Efficacy of MTP-131 for Treatment of Mitochondrial Disease in Subjects From the MMPOWER Study 2016. NCT02805790
13. A Trial to Evaluate Safety and Efficacy of Elamipretide Primary Mitochondrial Myopathy Followed by Open-Label Extension 2017. NCT03323749
14. ReCLAIM-2 Study to Evaluate Safety,Efficacy & Pharmacokinetics of Elamipretide in Subjects With AMD With Non-central GA 2019. NCT03891875

Every identifier above is resolved against PubMed, Crossref or ClinicalTrials.gov at build time, and the title returned by the register is compared with the title stored here. A page does not publish if a reference fails to resolve.

Research-Use Information

For in vitro research use only. This material is a laboratory reagent. It is not a drug, food, dietary supplement, or cosmetic and is not for human or veterinary use, including ingestion, injection, or any other administration. No information on this page describes or implies any effect in humans or animals. Sold only to researchers under our Terms of Sale.

Related laboratory reagent: SS-31 specifications and lot documentation