SS-31 10mg (Elamipretide)

SS-31 is a synthetic tetrapeptide with the sequence D-Arg-Dmt-Lys-Phe-NH2, where Dmt is 2',6'-dimethyltyrosine and the C-terminus is an amide rather than a free acid. The free base is C32H49N9O5 at 639.8 g/mol, CAS 736992-21-5, PubChem CID 11764719. It carries a net charge of 3+ at physiological pH, and that charge, combined with two aromatic side chains in alternating positions, is the whole basis of how it behaves in a cell.

The compound is better known in the clinical literature as elamipretide. It has also been published as MTP-131 and as Bendavia, and since September 2025 it has a trade name, Forzinity. All four names describe the same molecule. SS-31 is the name it was given at Cornell, where Hazel Szeto and Peter Schiller synthesised a series of aromatic-cationic peptides in the early 2000s; SS is for Szeto and Schiller, and the number is the compound's index in that series rather than a strength or a dose.

SS-31 has one of the longest human research records of any compound in this catalogue: twenty-one registered studies on ClinicalTrials.gov spanning Phase 1 through Phase 3 and covering reperfusion injury, heart failure, mitochondrial myopathy, Barth syndrome, geographic atrophy, Leber hereditary optic neuropathy, Fuchs corneal dystrophy, Friedreich ataxia and renal artery stenosis. Most of those trials missed their primary endpoints. The programme nonetheless produced a first approval, granted under accelerated approval in the United States in September 2025 for Barth syndrome in patients weighing 30 kg or more.

SS-31 has no receptor. It is not a signalling peptide and nothing on the cell surface recognises it. Zhao and colleagues showed in 2004 that peptides built on this alternating aromatic and basic motif cross the plasma membrane without a carrier and then concentrate roughly 1000-fold in the inner mitochondrial membrane relative to the surrounding medium. In neuronal N2A cells they blocked tert-butylhydroperoxide toxicity with EC50 values in the nanomolar range, and in isolated mitochondria they prevented calcium-induced swelling and cytochrome c release. Analogues built without the dimethyltyrosine residue neither suppressed mitochondrial reactive oxygen species nor prevented myocardial stunning in the ex vivo heart, which is the first evidence that the aromatic residue is structural to the effect and not decorative.

The target was identified nine years later. Birk and colleagues, working in Szeto's laboratory, made a polarity-sensitive fluorescent analogue of SS-31 and used it to show high-affinity binding to cardiolipin, the anionic phospholipid found almost exclusively on the inner mitochondrial membrane and required for cristae curvature. Cardiolipin also decides what cytochrome c does. Bound to cardiolipin in the normal conformation, cytochrome c is an electron carrier; when the interaction is perturbed, cytochrome c acquires peroxidase activity and begins oxidising the cardiolipin around it, which is the committed step toward cristae collapse and apoptosis. The SS-31 and cardiolipin complex inhibited that peroxidase activity by protecting the heme iron. In rats pretreated before renal ischaemia, cristae membranes stayed intact, mitochondria did not swell, ATP recovered promptly on reperfusion, and the actin cytoskeleton and tubular barrier function were restored.

This is why calling SS-31 an antioxidant is misleading, even though almost every product page does. The 2004 paper called the series peptide antioxidants because dimethyltyrosine is a radical scavenger, and the label stuck. A 2025 mechanistic review by Sabbah and nine co-authors states the position directly: the initial descriptions of the mechanism involved reactive oxygen species scavenging, and the last ten years have replaced that with a structural account in which the peptide modulates the electrostatic potential of the inner membrane and the assembly of cardiolipin-dependent protein complexes. The reduction in reactive oxygen species that laboratories measure is downstream of restored electron transport, not the result of scavenging radicals after they form. A compound that scavenged radicals would work in any oxidatively stressed compartment; SS-31 does essentially nothing outside mitochondria.

The cardiolipin account is not the last word. A genome-scale CRISPR screen published in 2024 by Silvaroli and colleagues, performed in human kidney-2 cells where SS-31 protects against cisplatin toxicity, returned phospholipid scramblase 3 as the gene the protection depends on. PLSCR3 is an understudied inner-membrane protein. SS-31 bound a previously uncharacterised N-terminal domain on it and stimulated its scramblase activity, and in tubular-epithelial-specific Plscr3 knockout mice the protective effect of SS-31 in cisplatin and rhabdomyolysis kidney injury disappeared completely, while baseline kidney function was unaffected. Whether PLSCR3 engagement is a second mechanism, a consequence of the lipid environment SS-31 creates, or the actual proximal event with cardiolipin binding as the readout, is open.

The Szeto-Schiller peptides came out of opioid peptide chemistry rather than mitochondrial biology. Peter Schiller's laboratory had been building analogues of dermorphin, and 2',6'-dimethyltyrosine was one of the unnatural residues in that toolbox. Hazel Szeto's group at Cornell found that certain of these analogues crossed cell membranes without a transporter and, more surprisingly, concentrated inside mitochondria. The series was numbered in synthesis order, which is why SS-02, SS-20 and SS-31 appear in the literature as distinct compounds. They are different molecules, not different strengths of one molecule.

That numbering matters for reading the older papers. SS-20 lacks the dimethyltyrosine residue and behaves differently in oxidative assays while still reaching mitochondria, which is what allowed the 2004 work to separate targeting from activity. Zhao and colleagues reported that analogues without dimethyltyrosine failed to suppress mitochondrial reactive oxygen species, failed to inhibit swelling, and failed to prevent myocardial stunning in an ex vivo heart preparation, while the parent compounds succeeded. A paper describing SS-20 or SS-02 is not describing SS-31.

SS-31 was licensed to Stealth BioTherapeutics, which developed it under the code MTP-131 and the name Bendavia for the cardiology programme, then renamed it elamipretide once the mitochondrial disease indications took priority. The 2016 EMBRACE-STEMI publication uses MTP-131 throughout; the 2023 MMPOWER-3 publication uses elamipretide throughout. Both describe the same tetrapeptide.

The founding paper is titled Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane, and that title is responsible for a great deal of subsequent confusion. Dimethyltyrosine is a phenolic residue and can scavenge radicals in a test tube, so the naming was reasonable in 2004. What the following two decades established is that scavenging is not how the compound produces its effects in tissue.

The distinction is testable and has been tested. A radical scavenger works wherever radicals are, in proportion to how much of it is present. SS-31 is inert in the cytosol and acts only where cardiolipin is, which is the inner mitochondrial membrane and nowhere else in an animal cell. It reduces reactive oxygen species production at source, by keeping electron transport coupled, rather than mopping up species already formed. Birk's demonstration that the peptide and cardiolipin complex protects the heme iron of cytochrome c gives a specific chemical mechanism for that: cytochrome c that keeps its normal cardiolipin interaction stays an electron carrier, and cytochrome c that has been converted into a peroxidase generates oxidised cardiolipin and destroys the membrane it sits in.

The 2025 review by Sabbah and colleagues, written by nine investigators across cardiology, biophysics and mitochondrial medicine, states the correction plainly and adds what has replaced it: modulation of inner-membrane electrostatic potential and of the assembly of cardiolipin-dependent protein complexes. Product descriptions that lead with free radical scavenging are describing the 2004 title, not the current model.

Twenty-one studies of elamipretide are registered on ClinicalTrials.gov. Read as a set, they describe a compound with a consistent safety profile and an inconsistent efficacy profile, and the pattern of which endpoints moved is more informative than any single result.

The cardiology programme produced two clean negatives. EMBRACE-STEMI (NCT01572909) infused the peptide during primary percutaneous coronary intervention in first anterior ST-elevation myocardial infarction and found no reduction in infarct size by creatine kinase-MB release, and no signal in the prespecified MRI, angiographic, electrocardiographic or clinical endpoints. PROGRESS-HF (NCT02788747) gave 4 mg or 40 mg daily for 28 days to 71 patients with reduced ejection fraction and found no change in left ventricular end-systolic volume. A larger Phase 2 in heart failure with 308 participants (NCT02914665) ran alongside them.

The mitochondrial myopathy programme produced a near miss, a near miss, and a definitive negative. MMPOWER, at 36 participants, found a 64.5 m 6-minute walk advantage at the highest intravenous dose that fell just short of significance (p = 0.053). MMPOWER-2, a 30-participant crossover at 40 mg daily for four weeks, found a 19.8 m advantage that also missed (p = 0.0833) while patient-reported fatigue measures moved clearly. MMPOWER-3 then enrolled 218 participants for 24 weeks and found a 6-minute walk difference of -3.2 m and no change in the fatigue score, and is classified as Class I evidence of no effect. The registry lists MMPOWER-3 (NCT03323749) as terminated.

The ophthalmology programme has repeatedly missed primary endpoints while producing a structural signal. ReCLAIM-2 missed both primaries and reported a 43 percent reduction in progression of ellipsoid zone attenuation, a measure of photoreceptor loss, at nominal significance. The topical formulation studied in 12 patients with m.11778G>A Leber hereditary optic neuropathy did not improve best-corrected visual acuity against vehicle in the treated eye over 52 weeks, though a post hoc central visual field analysis favoured treatment. A Phase 3 in age-related macular degeneration, ReNEW (NCT06373731, 313 participants), is active and not recruiting, and uses the ellipsoid zone endpoint that ReCLAIM-2 developed.

Two later Phase 3 programmes followed the genotype logic rather than the indication logic. NuPOWER (NCT05162768) enrolled 102 participants with primary mitochondrial disease caused by nuclear DNA mutations, the subgroup that moved in the MMPOWER-3 post hoc analysis, and completed in December 2024; no results have been posted to its registry record. A Phase 4 study in Barth syndrome (NCT07531251) and a Phase 2 in healthy ageing and physical function (NCT07275424) were both recruiting as of this writing.

Barth syndrome is the indication where the mechanism and the disease line up exactly. It is an X-linked disorder caused by loss-of-function variants in TAZ, the gene encoding the transacylase that remodels immature cardiolipin into its mature form. Patients accumulate monolysocardiolipin and are depleted of tetralinoleoyl cardiolipin, and the clinical picture is cardiomyopathy, skeletal muscle weakness and neutropenia. A compound whose only known target is cardiolipin was an obvious candidate.

TAZPOWER tested it in 12 patients, which is a large fraction of the known worldwide population. The blinded 12-week crossover missed both primary endpoints. In the open-label extension the same patients improved by 95.9 m on the 6-minute walk at 36 weeks and by a cumulative 96.1 m at week 168, with gains in knee extensor strength, three-dimensional left ventricular volumes and the monolysocardiolipin to cardiolipin ratio. That pattern, nothing in 12 weeks and a large effect over years, is compatible with a slow structural mechanism and is also compatible with the open-label design; a separate propensity-matched natural history study was run precisely because of that ambiguity. It compared 8 treated patients with 19 untreated controls and reported a 91.0 m 6-minute walk difference at week 76 (p = 0.0005) and handheld dynamometry differences of 40.8 N at 64 weeks and 56.7 N at 76 weeks.

That evidence package, an unblinded extension plus a natural history control, is what supported the September 2025 accelerated approval in the United States, for improving muscle strength in adult and paediatric Barth syndrome patients weighing 30 kg or more. It is the first disease-specific approval for the condition, and the approved product is the hydrochloride salt. Accelerated approval is a conditional pathway that requires confirmatory evidence, which is what the Phase 4 study is for.

The ageing literature on SS-31 is unusual in the speed of the effects reported. Siegel and colleagues gave old mice a single treatment and measured skeletal muscle energetics one hour later using combined optical and 31P magnetic resonance spectroscopy. Resting and maximal mitochondrial ATP production, the phosphate-to-oxygen coupling ratio and the phosphocreatine to ATP ratio all returned to young levels. Young mice showed no change, which is the control that makes the result interesting: the peptide corrects a deficit rather than raising a normal value.

Chiao and colleagues extended this to the heart with an eight-week course in old mice, reporting substantial reversal of established diastolic dysfunction, normalised mitochondrial proton leak, reduced cardiomyocyte reactive oxygen species and a shift toward a reduced protein thiol state. The mechanistic control in that study is the most informative part: old mice given late-life viral expression of mitochondrial-targeted catalase gained the same functional benefit, and adding SS-31 to those animals gained nothing more, which places both interventions on an overlapping mitochondrial oxidative pathway.

The human ageing data are much thinner. A 41-participant Phase 2 (NCT02245620) gave a single intravenous dose to elderly subjects with prior evidence of mitochondrial dysfunction and measured hand skeletal muscle energetics and performance. A 2025 study reported that in mice the cardiac and skeletal muscle functional improvements arrived without detectable changes in tissue epigenetic or transcriptomic age, which is a useful separation: the compound appears to change how mitochondria perform without changing the molecular clocks used to define biological age.

SS-31 sits in a different pharmacological category from the mitochondria-associated peptides it is usually shelved beside. MOTS-c and humanin are mitochondrial-derived peptides: they are encoded in mitochondrial DNA, they are secreted, and they act through cellular signalling, MOTS-c through AMPK and the folate cycle. SS-31 is a synthetic molecule with no genomic origin, no receptor and no signalling role. It works by sitting in a membrane.

It also differs from the small-molecule mitochondrial antioxidants it is grouped with. MitoQ and SkQ1 are lipophilic cations that use the mitochondrial membrane potential to drive accumulation, which means their uptake collapses in exactly the depolarised mitochondria a researcher most wants to reach. SS-31 accumulates by binding cardiolipin rather than by following the potential gradient, which is the reason ischaemic and dysfunctional mitochondria are within its reach. Mitochondrial uncouplers such as BAM-15 are the opposite intervention again: they deliberately dissipate the proton gradient to raise respiration, where SS-31 is trying to preserve coupling.

The practical consequence for study design is that SS-31 has no meaningful effect on a healthy mitochondrion. Siegel found nothing in young muscle, and Chiao found nothing additive in hearts already protected by mitochondrial catalase. Experiments comparing it against these other compounds need a genuine mitochondrial lesion in the model, or the null result is uninformative.

The number on a vial label and the number in the literature are not always the same quantity, and SS-31 is a compound where the gap is large enough to matter. Standard solid-phase synthesis with trifluoroacetic acid cleavage yields the peptide as a salt, and the counter-ion is usually acetate after ion exchange. Elamipretide monoacetate is C34H53N9O7 at 699.8 g/mol against 639.8 for the free base, so a nominal 10 mg of acetate salt corresponds to about 9.1 mg of peptide. The approved pharmaceutical product is the hydrochloride, C32H52Cl3N9O5 at 749.2 g/mol as the trihydrochloride, a different number again. A certificate of analysis that reports only HPLC purity says nothing about which of these the vial contains.

Identity confirmation for a tetrapeptide is straightforward and worth insisting on. Electrospray mass spectrometry should return a mass consistent with 639.8 for the free base, and the 3+ charge state means the multiply charged ions are prominent. Reversed-phase HPLC with ultraviolet detection at 214 nm resolves the peptide from deletion sequences; the two aromatic residues also give usable absorbance at 280 nm, which most tetrapeptides do not offer. The single D-amino acid at position 1 is the residue most worth verifying, since a batch epimerised at that position would be chromatographically similar and biologically different.

Lyophilised material is handled as a hygroscopic peptide powder: sealed, protected from light and moisture, and equilibrated to room temperature before the vial is opened so that condensation does not enter it. Aqueous solutions of short peptides are much less stable than the dry powder, and the amidated C-terminus, while it removes one route of degradation, does not make the molecule indefinitely stable in solution. Repeated freezing and thawing of aqueous stocks is the most common avoidable cause of assay drift with peptides of this size.