SS-31 10 mg

SS-31 is a synthetic tetrapeptide with the sequence D-Arg-Dmt-Lys-Phe-NH2, in which Dmt denotes 2',6'-dimethyl-L-tyrosine. Two of the four residues are non-standard. The N-terminal arginine is in the D configuration rather than the L configuration found in ribosomally synthesised protein, and the tyrosine carries methyl substituents at both ring positions flanking the phenolic hydroxyl. The C-terminus is an amide, not a free carboxylic acid. The guanidinium group of the arginine, the epsilon-amino group of the lysine and the free N-terminal amine are all protonated at physiological pH, so the molecule is polycationic, while the dimethyltyrosine and phenylalanine side chains are aromatic. Aromatic and basic residues therefore alternate along the chain. Zhao and colleagues described the structural motif of this peptide class as centring on alternating aromatic and basic amino acid residues, with dimethyltyrosine providing scavenging properties, and reported that analogues lacking dimethyltyrosine did not inhibit mitochondrial reactive oxygen species generation or swelling in their assays (Zhao et al., 2004). Molecular formula C32H49N9O5, molecular weight 639.80 g/mol.

The SS designation comes from the Szeto-Schiller series, named for Hazel Szeto and Peter Schiller, both authors on the 2004 paper that first characterised the class. The same molecule carries the International Nonproprietary Name elamipretide and appears throughout the literature under the development codes MTP-131, Bendavia and RX-31. It is catalogued as PubChem CID 11764719, KEGG D10925, DrugBank DB11981, UNII 87GWG91S09 and CAS 736992-21-5, the last of these being the free base; the hydrochloride carries a separate registry number. On 19 September 2025 the US Food and Drug Administration granted accelerated approval to Forzinity (elamipretide hydrochloride), sponsored by Stealth BioTherapeutics, for patients with Barth syndrome weighing at least 30 kg. The FDA stated that the accelerated approval rests on improvement in knee extensor muscle strength, an intermediate clinical endpoint, and that as a condition of approval the sponsor must conduct a post-approval randomised, double-blind, placebo-controlled trial to verify that the change in knee muscle strength translates into clinical benefit (FDA press announcement, 19 September 2025; FDA approval letter, NDA 215244).

The peptide is highly water-soluble. Szeto described the SS peptides as very water soluble yet remarkably cell permeable, and reported that uptake into isolated mitochondria was rapid and independent of mitochondrial membrane potential, in contrast with antioxidants delivered to the matrix by conjugation to delocalised lipophilic cations such as triphenylphosphonium (Szeto, 2014). Material supplied here is a lyophilised powder at ≥99% purity in a 10 mg vial, for laboratory research use only. It is not a pharmaceutical product and is not for human consumption.

The compound entered the literature as one of a set of cell-permeable peptide antioxidants designed to reach the inner mitochondrial membrane. Zhao and colleagues reported that these peptides concentrated 1000-fold in the inner mitochondrial membrane, and that in neuronal N2A cells they potently reduced intracellular reactive oxygen species and cell death caused by t-butylhydroperoxide, with half-maximal effect concentrations in the nanomolar range. In isolated mitochondria the same peptides were reported to decrease mitochondrial reactive oxygen species production, inhibit the permeability transition and swelling, and prevent calcium-induced cytochrome c release. The authors noted that analogues in which dimethyltyrosine was omitted did not inhibit mitochondrial reactive oxygen species generation or swelling and failed to prevent myocardial stunning in their ex vivo heart model (Zhao et al., 2004).

The molecular target was assigned nine years later. Birk and colleagues used a polarity-sensitive fluorescent analogue of SS-31 and reported that the peptide binds with high affinity to cardiolipin, the anionic phospholipid expressed on the inner mitochondrial membrane. In that work SS-31 inhibited the peroxidase activity of cytochrome c, and pretreatment of rats before renal ischaemia was reported to protect cristae membranes and prevent mitochondrial swelling, with rapid recovery of ATP on reperfusion (Birk et al., 2013). A later biophysical study revisited the interaction in model and mitochondrial membranes. Mitchell and colleagues found that the peptide partitioned into the membrane interfacial region with an affinity and lipid binding density directly related to surface charge, did not destabilise lamellar bilayers even at the highest binding concentrations tested, produced saturable alterations in lipid packing, and modulated the surface electrostatics of both model and mitochondrial membranes, including the distribution of divalent calcium at the interface (Mitchell et al., 2020).

Animal work has extended to aged tissue. Siegel and colleagues injected 5-month-old and 27-month-old mice intraperitoneally with saline or 3 mg/kg SS-31 and measured skeletal muscle energetics in vivo one hour later using combined optical and phosphorus-31 magnetic resonance spectroscopy. Age-related declines in resting and maximal mitochondrial ATP production, in the P/O coupling ratio and in the phosphocreatine to ATP ratio were reported to reverse within that hour, while no measurable effect was observed in the young cohort. The same report described a more reduced glutathione redox status, lower mitochondrial hydrogen peroxide emission, greater fatigue resistance in aged muscle one hour after injection, and increased whole-animal endurance capacity after eight days of treatment (Siegel et al., 2013).

The human trial record is substantial and mixed, and reading it in full matters more than reading any single result. In MMPOWER, a phase 1/2 multicentre randomised placebo-controlled dose-escalation study in 36 adults with genetically confirmed primary mitochondrial myopathy, participants were randomised to intravenous elamipretide at 0.01, 0.1 or 0.25 mg/kg/h, or placebo, over two hours in a dose-escalating sequence. Those receiving the highest dose walked a mean of 64.5 m further on the 6-minute walk test at day 5 against a change of 20.4 m in the placebo group, a difference that did not reach the conventional significance threshold (p = 0.053), alongside a dose-dependent increase across arms (p = 0.014) (Karaa et al., 2018). The phase 3 follow-up did not reproduce this. MMPOWER-3 randomised 218 participants 1:1, 109 per arm, to 40 mg/day subcutaneous elamipretide or placebo for 24 weeks and missed both primary endpoints: the between-group difference in least-squares mean change from baseline to week 24 in 6-minute walk distance was -3.2 m (95% CI -18.7 to 12.3; p = 0.69) and the difference in Primary Mitochondrial Myopathy Symptom Assessment total fatigue score was -0.07 (95% CI -0.10 to 0.26; p = 0.37). The investigators classified the result as Class I evidence of no effect on those two measures, while reporting that subcutaneous administration was well tolerated with most adverse events mild to moderate (Karaa et al., 2023).

Barth syndrome, a genetic condition caused by defects in TAZ that produce abnormal cardiolipin on the inner mitochondrial membrane, is where the molecule reached regulatory approval as a pharmaceutical. In TAZPOWER, 12 subjects were randomised in a placebo-controlled crossover design to 40 mg/day of elamipretide or placebo for 12 weeks, followed by a 4-week washout and 12 weeks on the opposite arm; in that randomised phase neither primary endpoint was met. Ten subjects continued into an open-label extension, of whom eight reached 36 weeks, and at that point the investigators reported a change of +95.9 m on the 6-minute walk test (p = 0.024) and -2.1 points on the Barth Syndrome Symptom Assessment (p = 0.031), together with reported improvements in secondary endpoints including knee extensor strength, patient global impression of symptoms and some cardiac parameters (Reid Thompson et al., 2021). The uncontrolled design of that extension phase is the reason the 2025 US accelerated approval was tied to an intermediate endpoint with a confirmatory randomised trial still outstanding. Beyond these programmes the published record on SS-31 is preclinical, spanning renal, cardiac, skeletal muscle and neural models. There is no published peer-reviewed work on research-grade material handled outside a controlled clinical setting, and nothing in the literature above addresses the storage, reconstitution or handling of the compound as supplied here.