SS-31 (Elamipretide)

What Is SS-31?

SS-31, known by the generic name elamipretide, is a synthetic mitochondria-targeting tetrapeptide that binds cardiolipin in the inner mitochondrial membrane. A 2025 review lists MTP-131 among its other designations and describes a structure that allows uptake into many cell types with highly selective mitochondrial targeting^[1].

Reviews describe elamipretide as a water-soluble, aromatic-cationic peptide that crosses the outer mitochondrial membrane and transiently localizes to the inner membrane, where it associates with cardiolipin^[2]. Through that interaction it has been studied as a way to stabilize cristae structure, reduce oxidative stress, and support ATP production^[1].

Unlike most compounds discussed as research peptides, elamipretide has reached regulatory approval. In September 2025 it received accelerated approval in the United States for Barth syndrome, an ultra-rare X-linked genetic disorder^[3]. All other applications remain investigational.

Chemical Structure and Molecular Identity

SS-31 is a four-residue peptide amide, D-Arg-Dmt-Lys-Phe-NH2, with the molecular formula C32H49N9O5 and a molecular weight of 639.8 g/mol. PubChem lists it under CID 11764719 with CAS number 736992-21-5 and InChIKey SFVLTCAESLKEHH-WKAQUBQDSA-N.

Two of the four residues are non-standard. The N-terminal arginine is the D-enantiomer, and the second residue, Dmt, is 2′,6′-dimethyltyrosine, a tyrosine with two methyl groups on its aromatic ring. The C-terminus is amidated. Because of these features, SS-31 cannot be written as a standard one-letter amino-acid sequence.

• Alternating motif: basic (D-Arg), aromatic (Dmt), basic (Lys), aromatic (Phe)
• Charge: the N-terminal amine, the arginine guanidino group and the lysine side chain give a net charge of about +3 at physiological pH
• C-terminal amide: removes the negatively charged carboxylate

This alternating layout underlies the aromatic-cationic description used in the literature^[2]. PubChem also lists the synonym Szeto-Schiller peptide, the source of the SS prefix. Drug-information literature describes the salt form as elamipretide hydrochloride^[4].

Research History and Development

Elamipretide moved from preclinical mitochondrial research into clinical trials in heart failure, mitochondrial myopathy and Barth syndrome, and received its first approval in 2025. It has been developed by Stealth BioTherapeutics for disorders featuring mitochondrial dysfunction^[3].

Preclinical work covered heart failure, neurodegeneration, ischemia-reperfusion injury, metabolic syndromes, and muscle atrophy and weakness^[1]. Named clinical programs include PROGRESS-HF, TAZPOWER, MMPOWER-3 and ReCLAIM^[1]. Cardiovascular research was an early focus, with animal heart failure models followed by early-phase human trials^[5].

The phase 3 MMPOWER-3 trial in primary mitochondrial myopathy, published in 2023, did not meet its primary endpoints^[6]. A post hoc analysis then looked for genotype-specific responders to design a more targeted phase 3 trial^[7]. In September 2025 the US granted accelerated approval to improve muscle strength in adult and pediatric patients with Barth syndrome, the first disease-specific treatment for that condition, while phase 3 development continued in dry age-related macular degeneration and mitochondrial myopathies^[3].

Mechanisms Studied in Research

The central mechanism studied for SS-31 is selective binding to cardiolipin, a phospholipid of the inner mitochondrial membrane. Reviews report that this binding stabilizes cristae structure, reduces oxidative stress and enhances ATP production^[1].

Cardiolipin-cytochrome c interaction

Heart failure research frames the target as the cardiolipin-cytochrome c supercomplex. By stabilizing it, elamipretide is studied for maintaining cellular bioenergetics and preventing damage induced by reactive oxygen species, at a site where mitochondria link energy production with the initiation of programmed cell death^[5].

Reported effects by model

Terminology varies across papers. Some describe elamipretide as a mitochondrion-targeted antioxidant^[8], while the 2026 approval summary calls it a mitochondrial cardiolipin binder^[3].

Key Findings From Published Studies

Elamipretide has randomized human trial data, and the results are mixed: a pivotal myopathy trial missed its primary endpoints, while the compound gained accelerated approval for Barth syndrome. Animal studies span cardiac and neurological models.

Primary mitochondrial myopathy (human)

MMPOWER-3 was a phase 3, randomized, double-blind, placebo-controlled trial in 218 adults with genetically confirmed primary mitochondrial myopathy, randomized 1:1 to elamipretide or placebo for 24 weeks. Primary endpoints were change in six-minute walk test (6MWT) distance and total fatigue on the Primary Mitochondrial Myopathy Symptom Assessment. About 74% of participants had mitochondrial DNA alterations. The trial did not meet its primary endpoints^[6].

In the post hoc analysis, participants with nuclear DNA variants in mtDNA replisome genes, mostly POLG and TWNK, showed a 6MWT change of 25.2 ± 8.7 m with elamipretide versus 2.0 ± 8.6 m with placebo (p = 0.06). In the replisome subgroup with chronic progressive external ophthalmoplegia, the change was 37.3 ± 9.5 m versus −8.0 ± 10.7 m (p = 0.0024)^[7]. These are post hoc, hypothesis-generating results.

Heart failure (animal and early human)

Elamipretide increased left ventricular ejection fraction in dog models of heart failure with reduced ejection fraction and prevented left ventricular remodeling in rats. In early-phase clinical trials it produced no severe adverse events and showed improvements in cardiac hemodynamics in the highest-dose groups^[5].

Neuroinflammation (animal)

In mice given lipopolysaccharide, elamipretide significantly ameliorated learning and memory impairment in the Morris water maze and contextual fear conditioning tests. It also reversed changes in key synaptic-signaling proteins and increased synaptic structural complexity in the hippocampus^[8].

Barth syndrome

A 2022 review argued that available evidence supports durable effects on cardiomyopathy progression after treatment stops and an ability to structurally reverse-remodel the failing left ventricle^[2].

Because SS-31 contains a D-amino acid and the non-standard residue Dmt, researchers confirm its identity with HPLC and mass-spectrometry certificates of analysis.

Because SS-31 contains a D-amino acid and the non-standard residue Dmt, researchers confirm its identity with HPLC and mass-spectrometry certificates of analysis.

Regulatory and Research Status

Elamipretide is FDA approved under accelerated approval for one indication, Barth syndrome, and remains investigational for all other conditions. The September 2025 approval covers improving muscle strength in adult and pediatric patients with Barth syndrome^[3]. US accelerated approval generally requires confirmatory evidence of clinical benefit.

Phase 3 programs in dry age-related macular degeneration and mitochondrial myopathies were under way at the time of the approval summary^[3], and a 2026 drug monograph on elamipretide hydrochloride appeared in the American Journal of Health-System Pharmacy^[4].

Research-grade SS-31 is not the approved drug product and is not covered by its approval. A 2026 narrative review in Sports Medicine listed SS-31 among peptides marketed directly to patients and cautioned that, for unapproved peptides, rigorous human safety data are scarce^[11].

Open research questions include which patient genotypes respond to treatment, as the MMPOWER-3 post hoc work suggests^[7], and the long-term efficacy and safety of the drug, which reviews identify as areas needing further study^[1].