SS-31 (Elamipretide)

What SS-31 is

SS-31 is a synthetic tetrapeptide with the sequence D-Arg-Dmt-Lys-Phe-NH2, where Dmt is 2',6'-dimethyltyrosine, a non-proteinogenic tyrosine analogue, and the C-terminus is an amide. It belongs to the Szeto–Schiller series, a family of short aromatic-cationic peptides developed by Hazel Szeto at Weill Cornell and Peter Schiller at the Montreal Clinical Research Institute. The series began as opioid-receptor ligands; SS-31 was selected because it kept the cell-penetrating and mitochondria-concentrating properties of its parents while lacking meaningful opioid activity [1, 2]. In the pharmaceutical literature the same molecule appears as elamipretide, MTP-131 and, earlier, Bendavia, all names from the development programme run by Stealth BioTherapeutics. In September 2025 the United States Food and Drug Administration granted accelerated approval to an elamipretide injection, under the brand name Forzinity, for Barth syndrome [16]. The research material described on this page is not that product; the distinction is discussed under regulatory status below.

The alternating aromatic-cationic motif, with two basic residues (D-arginine and lysine) interleaved with two aromatic ones (Dmt and phenylalanine), gives it a net charge of +3 at physiological pH and a hydrophobic face. That combination lets it cross plasma membranes without a transporter and, according to the discovering group, concentrate several-hundred-fold in the inner mitochondrial membrane [1]. The D-configured N-terminal arginine and the C-terminal amide confer resistance to aminopeptidases and carboxypeptidases respectively, which is why a peptide this short survives in plasma for hours rather than minutes.

Research-grade SS-31 is supplied as a white lyophilised powder, usually as a trifluoroacetate or acetate salt. The licensed product is formulated as the hydrochloride. The reference identifiers for the free peptide are given in the table and the values on any batch certificate should agree with them.

How the literature describes its mechanism

SS-31 is one of the few peptides in the catalogue with a specific, independently examined molecular target, and it is a lipid rather than a receptor: cardiolipin, which makes up around a fifth of the inner mitochondrial membrane and is almost absent elsewhere in the cell.

The first description came from Zhao and colleagues in the Journal of Biological Chemistry in 2004. They showed that SS-02 and SS-31 enter cells in an energy-independent manner and partition into the inner mitochondrial membrane, that they scavenge hydrogen peroxide and peroxynitrite and inhibit lipid peroxidation in vitro, and that they prevent the mitochondrial permeability transition, mitochondrial swelling and cytochrome c release in isolated mitochondria. In neuronal cell lines they reduced apoptosis induced by tert-butylhydroperoxide, and in an isolated perfused guinea-pig heart they reduced ischaemia–reperfusion injury [1]. The antioxidant chemistry was attributed to the dimethyltyrosine phenol and the mitochondrial concentration to the cationic charge.

That picture was revised by the same group a decade later. Birk and colleagues, in the Journal of the American Society of Nephrology in 2013, reported that SS-31 binds selectively to cardiolipin through a combination of electrostatic and hydrophobic interactions, and that the peptide does not accumulate in mitochondria depleted of cardiolipin. In their hands SS-31 inhibited the peroxidase activity that cytochrome c acquires when bound to cardiolipin, protected cristae in ischaemic rat kidney and accelerated ATP recovery after reperfusion [3]. A companion paper in the British Journal of Pharmacology in 2014 proposed that by binding the cytochrome c–cardiolipin complex, SS-31 keeps cytochrome c in its native electron-carrying conformation, increases state 3 respiration and ATP synthesis in isolated mitochondria, and reduces electron leak and superoxide production at the source rather than scavenging it afterwards [4]. Szeto's review from the same year sets out this "cardiolipin-protective" framework in full and is the most useful single account of the group's thinking [2].

Two independent laboratories have since examined the mechanism with different tools. Mitchell and colleagues at the University of Connecticut, in the Journal of Biological Chemistry in 2020, used model lipid bilayers and showed that SS-31 binds membranes with a preference for anionic lipids rather than a strict cardiolipin specificity, inserts near the lipid head groups, and reduces the negative surface potential of the membrane. They argued that modulation of membrane electrostatics is a key component of the peptide's action, and that direct antioxidant chemistry is unlikely to explain its effects at the concentrations used in cells [5]. Chavez and colleagues at the University of Washington, in PNAS the same year, used chemical cross-linking mass spectrometry in intact mitochondria from aged mouse hearts and identified a set of inner-membrane proteins in proximity to SS-31, including subunits of ATP synthase, the ADP/ATP carrier, creatine kinase and 2-oxoglutarate dehydrogenase, all of which are known to associate with cardiolipin [6]. Both papers are compatible with the Szeto model but shift its emphasis from a single partner to the membrane environment of a protein neighbourhood.

For an in-vitro programme the readouts in the literature are mitochondrial membrane potential, oxygen consumption and ATP synthesis in isolated mitochondria or permeabilised cells, cristae morphology by electron microscopy, cytochrome c peroxidase activity, lipid peroxidation, mitochondrial superoxide reporters, and cell survival under oxidative or ischaemic stress. Effects are typically reported in the nanomolar to low micromolar range, and results depend on medium composition and serum proteins.

The research record

The honest summary is that the preclinical record is consistent and the clinical record is mixed, with a single approval resting on a narrow endpoint.

Preclinical ischaemia–reperfusion. The original 2004 paper included an isolated guinea-pig heart model [1]. Szeto and colleagues followed this in 2011 with a rat model of 45-minute bilateral renal ischaemia, reporting that SS-31 accelerated the recovery of ATP, reduced tubular cell apoptosis and necrosis, preserved mitochondrial structure and improved renal function after reperfusion [7]. Kloner and colleagues, in the Journal of the American Heart Association in 2012, tested the compound under the name Bendavia in rabbit coronary occlusion and in isolated guinea-pig hearts, reporting smaller infarcts relative to the area at risk and less microvascular no-reflow when the peptide was given before reperfusion [8]. This work was done by or with the originating laboratory and the sponsor, which should be borne in mind, but the results are internally consistent.

Early clinical work. EMBRACE STEMI, a phase 2a trial published in the European Heart Journal in 2016, randomised nearly 300 patients undergoing primary percutaneous coronary intervention to intravenous MTP-131 or placebo. The primary endpoint, infarct size estimated from creatine kinase-MB release over 72 hours, was not met, and none of the secondary cardiac endpoints differed between groups [9]. PROGRESS-HF, a phase 2 trial in heart failure with reduced ejection fraction published in the Journal of Cardiac Failure in 2020, randomised around 70 patients to 28 days of subcutaneous elamipretide at two dose levels or placebo. The primary endpoint, change in left ventricular end-systolic volume, did not differ from placebo [10].

Primary mitochondrial myopathy. The programme then moved to genetic mitochondrial disease. MMPOWER-3, a phase 3 trial published in Neurology in 2023, randomised 218 adults to 24 weeks of daily subcutaneous elamipretide or placebo. Neither primary endpoint was met: the difference in six-minute walk distance was −3.2 m (95% CI −18.7 to 12.3) and the difference in the total fatigue score was negligible. A prespecified subgroup analysis suggested an effect in patients with nuclear DNA defects but not in the majority with mitochondrial DNA mutations, and the authors present this as hypothesis-generating [11]. The topline failure was announced in late 2019 and the indication was not pursued.

Barth syndrome. Barth syndrome is an X-linked disorder of the TAZ gene, whose product remodels cardiolipin acyl chains, and it is the one indication in which the target lipid is itself the lesion. TAZPOWER, published in Genetics in Medicine in 2021 by Reid Thompson and colleagues, was a crossover trial in 12 males followed by an open-label extension. In the 12-week crossover phase the primary endpoints, six-minute walk distance and a fatigue scale, did not differ between elamipretide and placebo. In the open-label extension, improvements in walk distance and in several secondary measures emerged over 36 weeks and persisted [12]. The trial is tiny, the controlled phase was negative and the positive findings are open-label, which the authors acknowledge; the argument that a slowly progressive disease needs longer than 12 weeks to respond is reasonable but untested in a controlled design.

The 2025 approval. After a protracted review, the FDA granted accelerated approval to elamipretide injection, as Forzinity, on 19 September 2025, for Barth syndrome in patients weighing at least 30 kg. The approval was based on improvement in knee extensor muscle strength, which the agency regarded as reasonably likely to predict clinical benefit, and it is conditional on a post-approval randomised, double-blind, placebo-controlled trial to confirm that benefit [16]. Accelerated approval on a surrogate endpoint in a dozen patients is a legitimate pathway for an ultra-rare disease, but it is not demonstrated efficacy, and the licence does not settle the question TAZPOWER left open.

Dry age-related macular degeneration. The ophthalmic programme is the largest still running. ReCLAIM, a single-centre open-label phase 1 study in 19 patients with non-central geographic atrophy, published in Ophthalmology Science in 2022, reported that daily subcutaneous elamipretide was tolerated and was associated with improvements in low-luminance visual acuity, with the authors noting that the analyses were exploratory and uncontrolled [13]. ReCLAIM-2, a randomised, placebo-controlled phase 2 trial in 176 patients published in the same journal in 2025, did not meet either primary endpoint: neither low-luminance visual acuity nor geographic atrophy area differed significantly from placebo at 48 weeks. An exploratory analysis found slower progression of ellipsoid-zone attenuation on optical coherence tomography, and the sponsor has adopted that measure as the primary endpoint of a phase 3 trial, ReNEW, which is fully enrolled with a readout expected in 2027 [14]. Choosing a phase 3 endpoint from the exploratory analysis of a failed phase 2 is a recognised but risky decision, and the result should be awaited.

Taking the record as a whole. SS-31 has a defined and independently corroborated molecular target, a consistent preclinical record in ischaemia–reperfusion and mitochondrial dysfunction, a clinical safety profile across several hundred patients dominated by injection-site reactions, and a series of controlled trials that have, with one narrow exception, failed to meet their primary endpoints. That is a legitimate basis for in-vitro work on mitochondrial bioenergetics and membrane biology. This page makes no therapeutic claims.

Regulatory status in the United Kingdom

Elamipretide is not licensed as a medicine in the United Kingdom. The Medicines and Healthcare products Regulatory Agency has granted no marketing authorisation, there is no European Medicines Agency authorisation, and the sponsor's own statements note that no therapy for Barth syndrome is approved in the European Union [16]. The United States approval applies only there and only to the sponsor's hydrochloride injection, made under pharmaceutical good manufacturing practice. The research-grade SS-31 supplied by BuyUK Peptides is not Forzinity and is supplied as a research chemical for in-vitro laboratory use under the Terms of Sale. It is not for human or veterinary administration. Purchasers must be 18 or over and are responsible for ensuring their use of the material complies with the laws and institutional rules that apply to them. Our guide to the UK rules on research compounds sets this out in more detail.

Elamipretide is not named on the World Anti-Doping Agency's 2026 Prohibited List, and UK Anti-Doping's summary of the changes for 2026 does not mention it or any mitochondrial-targeting peptide; the only mitochondrial reference in the 2026 changes concerns the transfer of cell components such as mitochondria under the gene and cell doping heading [15]. Before September 2025 it would have fallen under the general S0 category for substances with no regulatory approval anywhere; whether a single accelerated approval removes it from S0 is a matter of WADA's interpretation, and any researcher subject to anti-doping rules should take advice from UKAD rather than rely on this page.

Handling, storage and stability

SS-31 is supplied lyophilised in a glass vial with a rubber stopper and an aluminium flip-off crimp. As a short, highly water-soluble, cysteine-free peptide it is straightforward to reconstitute, but two features of its chemistry call for care: the Dmt phenol is susceptible to oxidation, and the cationic, amphipathic character that lets it enter cells also lets it adsorb to surfaces.

Sealed vial. Store at 2–8 °C for routine use and at −20 °C or below for storage beyond a few months. Protect from light. Avoid repeated freeze–thaw cycles. Allow a refrigerated vial to reach room temperature before opening, so that moisture does not condense onto the cake. Vendor datasheets report that the powder tolerates short periods at ambient temperature in transit without measurable loss.

Reconstitution. For in-vitro work the compound is reconstituted in sterile water, phosphate-buffered saline, or the assay buffer. A vendor datasheet reports solubility of around 100 mg/mL in water, far above any concentration a laboratory will need. Add the solvent down the side of the vial and swirl gently; the cake should clear immediately. Sonication is unnecessary. The reconstitution calculator gives the volume to add for a target concentration.

Reconstituted solution. Keep at 2–8 °C and protect from light. Dilute stock solutions of cationic peptides lose material to the walls of polypropylene and glass vessels; for working solutions below about 10 µM, low-binding tubes and pipette tips are advisable, and freshly prepared dilutions are preferable to stored ones. Aliquot concentrated stock into single-use volumes and freeze at −20 °C or −80 °C; use refrigerated solutions within a few weeks and discard anything that shows colour change, which can indicate oxidation of the phenol.

Solubility and assay considerations. In cell culture, serum proteins bind the peptide to some extent, and the published mechanism work was done in defined media or with isolated mitochondria for that reason [3, 4, 5]. For filtration use a low-binding 0.22 µm membrane (PVDF or PES); nylon and nitrocellulose retain cationic peptides.

What a sound certificate for SS-31 looks like

Every batch we release carries an independent certificate of analysis, and the figures from it are transcribed on the product page and in the certificate register. For SS-31 a certificate should contain the following, and a reader should be able to check each item against this monograph.

Purity by RP-HPLC. Reversed-phase HPLC on a C18 column with UV detection at 214 or 220 nm reports purity as the area of the main peak as a percentage of all integrated peaks. The Dmt residue also absorbs at 280 nm, which offers a useful second wavelength. A good batch of SS-31 shows a single dominant peak with purity of 98% or above; for a tetrapeptide 99% is routine. The impurities to look for are the L-arginine diastereomer, which elutes close to the main peak, and the des-amide acid from hydrolysis of the C-terminal amide. A certificate that shows the chromatogram is more informative than one that reports a number alone.

Identity by LC-MS. Electrospray mass spectrometry confirms that the main peak has the expected mass. For SS-31 the average molecular weight is 639.80 Da and the monoisotopic mass is 639.39 Da. A tribasic peptide of this size typically appears as the doubly charged [M+2H]2+ ion at about 320.7 and the triply charged [M+3H]3+ ion at about 214.1, with the singly charged [M+H]+ at about 640.4 also commonly observed. The observed mass should agree with the theoretical value to within about 0.3 Da. A mass one dalton higher than expected would suggest the des-amide impurity; a mass 28 Da lower would suggest the tyrosine analogue has been substituted for Dmt and should be treated as a failure of identity.

Net peptide content and counter-ion. Lyophilised SS-31 contains bound water and counter-ions, and because the peptide carries three positive charges the counter-ion fraction is large: a trifluoroacetate salt of a 640 Da peptide can be 25–35% counter-ion by mass. Net peptide content, where reported, expresses the fraction that is actual peptide, and it matters for a compound this small. The certificate should state whether the material is the trifluoroacetate or the acetate; residual trifluoroacetate is itself bioactive in some mitochondrial assays and some laboratories prefer the acetate for that reason.

Chiral purity. Because the N-terminal arginine is D-configured, a certificate that confirms the stereochemistry adds confidence that the material is SS-31 rather than its all-L analogue, which has different pharmacology and much shorter plasma stability.

Endotoxin. Where the batch has been tested, a limulus amoebocyte lysate (LAL) result is reported in endotoxin units per milligram. Endotoxin alters mitochondrial respiration in immune and endothelial cells and would confound the assays in which SS-31 is studied.

Our guide to reading a certificate of analysis goes through a complete report line by line.

Related compounds

SS-31 sits in the catalogue alongside MOTS-c, a mitochondrial-derived peptide encoded in the mitochondrial genome and studied for its effects on metabolic signalling, and NAD+, the redox cofactor on which the electron transport chain that SS-31 is said to protect depends. They are mechanistically quite different: SS-31 acts on the inner membrane lipid environment, MOTS-c on nuclear gene expression through AMPK and related pathways, and NAD+ as a substrate and cofactor. SS-31 is also the only one of the three with a defined molecular target supported by independent biophysical work [5, 6].

Frequently asked questions

Is SS-31 the same as elamipretide? Yes. SS-31, elamipretide, MTP-131 and Bendavia all refer to the tetrapeptide D-Arg-Dmt-Lys-Phe-NH2 [1, 2]. The research material differs from the licensed product Forzinity in its salt form, manufacturing standard and regulatory status.

Is it approved anywhere? In the United States, since 19 September 2025, under accelerated approval for Barth syndrome in patients weighing at least 30 kg, with a confirmatory trial required [16]. It has no licence in the UK or the EU.

Did the clinical trials work? The controlled trials in heart attack, heart failure, primary mitochondrial myopathy and dry AMD did not meet their primary endpoints [9, 10, 11, 14]. The Barth syndrome crossover phase was also negative on its primary endpoints, and the approval rests on a muscle-strength measure in a small open-label extension [12, 16].

What does it actually bind? Cardiolipin and, more generally, anionic inner-membrane lipids, according to the originating group and two independent laboratories [3, 5, 6]. There is no receptor.

Is it on the WADA list? It is not named on the 2026 Prohibited List [15]. Its status under the general S0 category after the US approval is a matter for WADA and UKAD rather than for this page.

Is this material for human use? No. It is supplied for in-vitro research only.

How long does a sealed vial last? Short lyophilised peptides of this kind are stable for years at −20 °C and for many months at 2–8 °C. The batch certificate reports the test date; the storage guidance on this page applies from receipt.

References

1. Zhao K, Zhao GM, Wu D, et al. Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury. Journal of Biological Chemistry. 2004;279(33):34682–34690. doi:10.1074/jbc.M402999200.
2. 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:10.1111/bph.12461.
3. 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:10.1681/ASN.2012121216.
4. 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. doi:10.1111/bph.12468.
5. 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. Journal of Biological Chemistry. 2020;295(21):7452–7469. doi:10.1074/jbc.RA119.012094.
6. Chavez JD, Tang X, Campbell MD, et al. Mitochondrial protein interaction landscape of SS-31. Proceedings of the National Academy of Sciences. 2020;117(26):15363–15373. doi:10.1073/pnas.2002250117.
7. Szeto HH, Liu S, Soong Y, et al. Mitochondria-targeted peptide accelerates ATP recovery and reduces ischemic kidney injury. Journal of the American Society of Nephrology. 2011;22(6):1041–1052. doi:10.1681/ASN.2010080808.
8. Kloner RA, Hale SL, Dai W, et al. Reduction of ischemia/reperfusion injury with Bendavia, a mitochondria-targeting cytoprotective peptide. Journal of the American Heart Association. 2012;1(3):e001644. doi:10.1161/JAHA.112.001644.
9. Gibson CM, Giugliano RP, Kloner RA, et al. EMBRACE STEMI study: a Phase 2a trial to evaluate the safety, tolerability, and efficacy of intravenous MTP-131 on reperfusion injury in patients undergoing primary percutaneous coronary intervention. European Heart Journal. 2016;37(16):1296–1303. doi:10.1093/eurheartj/ehv597.
10. Butler J, Khan MS, Anker SD, et al. Effects of elamipretide on left ventricular function in patients with heart failure with reduced ejection fraction: the PROGRESS-HF phase 2 trial. Journal of Cardiac Failure. 2020;26(5):429–437. doi:10.1016/j.cardfail.2020.02.001.
11. 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:10.1212/WNL.0000000000207402. PMID 37268435.
12. Reid Thompson W, Hornby B, Manuel R, et al. A phase 2/3 randomized clinical trial followed by an open-label extension to evaluate the effectiveness of elamipretide in Barth syndrome, a genetic disorder of mitochondrial cardiolipin metabolism. Genetics in Medicine. 2021;23(3):471–478. doi:10.1038/s41436-020-01006-8.
13. Mettu PS, Allingham MJ, Cousins SW. Phase 1 clinical trial of elamipretide in dry age-related macular degeneration and noncentral geographic atrophy: ReCLAIM NCGA study. Ophthalmology Science. 2022;2(1):100086. doi:10.1016/j.xops.2021.100086.
14. 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;5(1):100628. doi:10.1016/j.xops.2024.100628. PMID 39605874.
15. UK Anti-Doping. 2026 Prohibited List: summary of changes. Published 2025. ukad.org.uk.
16. US Food and Drug Administration. FDA grants accelerated approval for first treatment for Barth syndrome. Press announcement, 19 September 2025. fda.gov.

This monograph summarises the published literature for laboratory researchers. It is not medical advice, and nothing on this site is for human or veterinary use.