SS-31 (Elamipretide)

SS-31 is a synthetic aromatic-cationic tetrapeptide from the Szeto–Schiller series, with the sequence D-Arg-Dmt-Lys-Phe-NH2, where Dmt is 2,6-dimethyltyrosine. Its alternating cationic and aromatic residues allow it to cross cell membranes independently of a transporter and to concentrate in the inner mitochondrial membrane. Under the international non-proprietary name elamipretide it has been developed as a drug candidate by Stealth BioTherapeutics; the PubChem entry lists the free base as C32H49N9O5, 639.8 g/mol [8].

Cardiolipin binding and the proposed mechanism

Szeto's 2014 review in the British Journal of Pharmacology sets out the mechanism the field works from: SS-31 associates selectively with cardiolipin, the signature phospholipid of the inner mitochondrial membrane, through a combination of electrostatic and hydrophobic interactions. Cardiolipin normally anchors cytochrome c and supports cristae architecture and respiratory supercomplex assembly. When cardiolipin is oxidised or depleted, cytochrome c acquires peroxidase activity and electron transport becomes less efficient. The proposal is that peptide binding preserves the cytochrome c–cardiolipin interaction and cristae structure, restoring oxidative phosphorylation without acting as a conventional antioxidant scavenger [1].

Barth syndrome — the TAZPOWER programme

Barth syndrome is a rare X-linked disorder caused by variants in TAZ, in which remodelling of cardiolipin is defective — a mechanistically direct test of a cardiolipin-binding compound. TAZPOWER was a phase 2/3 randomised, double-blind, placebo-controlled crossover trial in 12 participants, each receiving 12 weeks of elamipretide and 12 weeks of placebo separated by a washout, followed by an open-label extension [2]. The randomised phase did not meet its co-primary endpoints of six-minute walk distance and total fatigue score. The open-label extension, reported in Genetics in Medicine in 2024, described changes in knee extensor strength and other measures over 168 weeks in a small, unblinded cohort [3].

Heart failure trials

Two controlled cardiology studies define what is known in a commoner disease. A 2017 Circulation: Heart Failure ascending-dose trial gave a single four-hour infusion to patients with reduced ejection fraction and reported that it was tolerated, with changes in left ventricular volumes at the highest dose that tracked plasma concentration [4]. PROGRESS-HF, a phase 2 trial published in the Journal of Cardiac Failure in 2020, randomised 71 patients with reduced ejection fraction to placebo or one of two daily subcutaneous doses for 28 days; the change in left ventricular end-systolic volume did not differ significantly from placebo, and no significant difference in ejection fraction was seen [5].

Why cardiolipin is the interesting target

Cardiolipin is a four-tailed phospholipid found almost exclusively in the inner mitochondrial membrane, where it makes up roughly a fifth of the lipid content. It stabilises the curvature of cristae, binds and positions several respiratory chain complexes, and holds cytochrome c loosely at the membrane surface. Its polyunsaturated acyl chains make it unusually vulnerable to peroxidation, and the oxidised species is both a poorer anchor for cytochrome c and a signal in apoptotic pathways. A compound that concentrates at this lipid therefore sits at a point where membrane architecture, electron transport efficiency and cell-death signalling converge, which explains why the same molecule has been examined in indications as different as a rare cardiolipin-remodelling disorder, heart failure, renal ischaemia and ophthalmic disease in the preclinical literature [1].

Regulatory history as of September 2026

The FDA granted accelerated approval to elamipretide hydrochloride for Barth syndrome on 19 September 2025, under NDA 215244, for improvement of muscle strength in adult and paediatric patients weighing at least 30 kg. The approval letter and the approved prescribing information are public on the FDA site [6][7]. The approval followed an earlier complete response and delay in the programme, and accelerated approval carries a confirmatory-evidence requirement. The action is specific to one ultra-rare mitochondrial disease; no approval exists for heart failure, ageing or any other indication.

What the research does not establish

The two randomised heart-failure studies were small and short, and PROGRESS-HF was negative on its imaging endpoint, so the compound is not established as a heart-failure therapy. The Barth syndrome approval rests on an open-label extension in roughly eight evaluable participants rather than on a positive randomised endpoint, which is why it was granted on an accelerated basis. No controlled human data support use in healthy ageing, exercise performance, cognition, or any cosmetic or metabolic indication, and reported adverse events in the trials included injection-site and hypersensitivity reactions. None of this material is supplied for human use.

Format. Supplied as a lyophilised powder in a sealed vial. The certificate of analysis states net peptide content; because the salt form and residual water contribute to vial mass, net peptide and vial mass differ.

Reconstitution. This is a short, highly basic peptide and dissolves readily in aqueous diluent. Add diluent slowly down the vial wall and swirl gently until clear; do not shake or vortex vigorously. Use the reconstitution calculator to determine the diluent volume for the working concentration required.

Storage. Keep the sealed lyophilised vial at −20°C, protected from light. Warm to room temperature before opening. After reconstitution, refrigerate and protect from light; prepare single-use aliquots rather than subjecting the stock to repeated freeze–thaw cycles.

Handling. Work aseptically with a fresh needle for each withdrawal, and label every aliquot with lot and date. For in-vitro laboratory research only — not for human or veterinary use.