SS-31 (Elamipretide) — Molecular Weight, Sequence & Clinical Evidence Reference

01What is SS-31 (Elamipretide)?

Elamipretide, better known in the research literature as SS-31, is a four-residue aromatic-cationic peptide containing the non-natural residue 2',6'-dimethyltyrosine. Its alternating cationic-aromatic structure allows it to cross cell membranes without a transporter and to concentrate in the inner mitochondrial membrane, where it binds cardiolipin — the signature phospholipid of that membrane — and is proposed to stabilise cristae architecture and improve electron transport efficiency.

The molecular record is clean, with the usual salt-form caveat: the free base is C32H49N9O5 at 639.80 g/mol, while the approved drug substance is a tris-hydrochloride salt at 749.2 g/mol. Doses in the clinical literature are expressed as free-base equivalents, so a quoted molecular weight alone does not tell you the peptide content of a vial.

This compound is in the pilot set specifically because its evidence profile is uncomfortable in a way most reference pages avoid. Elamipretide has been studied across primary mitochondrial myopathy, Barth syndrome, geographic atrophy and cardiac ischaemia-reperfusion, generating far more human data than the typical research peptide — and several of those programmes, including the primary endpoint in MMPOWER-3, did not deliver the result sought. A reference library that reports only the mechanism and omits the trial outcomes is not reporting the science.

02Molecular information

03Amino acid sequence

Structural modifications

Position 1 is D-arginine (D-stereoisomer, not the natural L form). Position 2 is Dmt, 2',6'-dimethyl-L-tyrosine, a non-proteinogenic residue; the FDA label writes the same residue as '2,6-dimethyl-L-tyrosyl' (the primes in the literature notation refer to the phenol ring positions). The C-terminus is a primary amide, not a free carboxylate: the label's formal chemical name is 'L-Phenylalaninamide, D-arginyl-2,6-dimethyl-L-tyrosyl-L-lysyl-, hydrochloride (1:3)'. The approved drug substance is the tris-hydrochloride salt. Because Dmt has no assigned single-letter code and position 1 is a D-residue, a standard one-letter string cannot represent this peptide without loss of information, which is why that field is null rather than approximated.

04Pharmacokinetic information

Half-life context

Human plasma elimination half-life of approximately 3 to 4 hours is stated in the FDA briefing document for NDA 215244 [7]; the same document gives Tmax 0.5 to 1 hour after subcutaneous dosing, absolute subcutaneous bioavailability approximately 92%, plasma protein binding approximately 39%, volume of distribution approximately 0.5 L/kg, and essentially complete renal recovery by 48 hours with no hepatic metabolism (sequential C-terminal degradation to inactive M1 and M2 metabolites). The approved FORZINITY prescribing information reports Tmax, bioavailability, Vd and protein binding but does not itself state a half-life value, so the 3 to 4 hour figure should be attributed to the briefing document rather than the label. A separate non-clinical figure of approximately 4 hours after intravenous administration in dogs is reported in the Alzheimer's Drug Discovery Foundation Cognitive Vitality review [8]. These plasma values must not be collapsed into a single universal number, and specifically must not be read as an effect-duration figure: the same review notes preclinical reports of roughly 5000-fold concentration of the peptide in mitochondria relative to other cellular compartments, so tissue and mitochondrial residence, and any pharmacodynamic effect duration, are not predicted by the plasma curve. No validated human pharmacodynamic half-life has been published. A phase 1 crossover study of injection-site reactions sampled only to 6 hours and did not compute a terminal half-life [9].

05Research focus

Primary research areas

• Cardiolipin binding at the inner mitochondrial membrane
• Mitochondrial bioenergetics and ATP recovery
• Primary mitochondrial myopathy
• Barth syndrome
• Geographic atrophy in dry age-related macular degeneration
• Ischemia-reperfusion and heart failure models

Research context

Elamipretide (SS-31, MTP-131) is a synthetic, cell-permeable, aromatic-cationic tetrapeptide, H-D-Arg-Dmt-Lys-Phe-NH2, in which Dmt is the non-proteinogenic residue 2',6'-dimethyltyrosine [1]. Its alternating cationic and aromatic residues allow membrane crossing without a transporter and accumulation at the inner mitochondrial membrane, where it associates with cardiolipin, the signature phospholipid of that membrane [1][2]. Birk and colleagues reported that SS-31 binds cardiolipin with high affinity, inhibits the peroxidase activity of the cytochrome c/cardiolipin complex, and in a rodent renal ischemia-reperfusion model preserved cristae architecture and accelerated ATP recovery on reperfusion [1]. Szeto subsequently framed the compound as a first-in-class cardiolipin-protective agent intended to restore mitochondrial bioenergetics rather than act as a general antioxidant [2]. Later biophysical work by Mitchell et al. refined the mechanism: in model bilayers and isolated mitochondria, SS-31 partitions into the membrane interfacial region with affinity and binding density related to surface charge, does not destabilise lamellar bilayers even at high occupancy, and modulates surface electrostatics and divalent-cation distribution, leading the authors to propose electrostatic tuning of the membrane interface rather than cardiolipin binding alone as a central component of its action [3]. This body of work is rodent, in vitro and biophysical, not human. The clinical programme, run by Stealth BioTherapeutics (renamed Mighty Therapeutics in 2026), tested subcutaneous elamipretide across several indications with largely negative pivotal outcomes. MMPOWER-3, a phase 3 trial in primary mitochondrial myopathy, randomised 218 participants to 40 mg/day subcutaneously or placebo for 24 weeks and missed both co-primary endpoints: the least-squares mean difference in 6-minute walk distance was -3.2 metres (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 paper is reported as Class I evidence of no effect [4]. The randomised crossover study in Barth syndrome (SPIBA-201/TAZPOWER Part 1, n = 12) likewise missed its primary endpoints (6-minute walk p = 0.97; total fatigue p = 0.89), with reviewers noting marked placebo-group improvement [7]. FDA nonetheless granted accelerated approval on 19 September 2025 for FORZINITY in Barth syndrome patients weighing at least 30 kg, based on knee extensor muscle strength as an intermediate clinical endpoint [5][6].

06Research evidence and limitations

Regulatory status

United States: FDA granted accelerated approval on 19 September 2025 to FORZINITY (elamipretide hydrochloride) injection, 80 mg/mL subcutaneous, indicated to improve muscle strength in adult and pediatric patients with Barth syndrome weighing at least 30 kg (NDA 215244, Stealth BioTherapeutics Inc., subsequently renamed Mighty Therapeutics). Approval was based on improvement in knee extensor muscle strength, an intermediate clinical endpoint; continued approval is contingent on verification of clinical benefit in a confirmatory trial, which the company stated in January 2026 it was on track to initiate in the first half of 2026. Commercial supply became available in late November 2025. FDA had previously delayed the decision and the application went through a resubmission cycle. The approval does not cover patients under 30 kg, for which the company reported planning further FDA discussions in early 2026 alongside an expanded access programme. Elamipretide is not approved for primary mitochondrial myopathy anywhere; the phase 3 MMPOWER-3 trial in that indication failed. A phase 3 trial (ReNEW) in geographic atrophy secondary to dry age-related macular degeneration is ongoing with a readout expected late 2027. No European Medicines Agency marketing authorisation was verified in this session; the January 2026 company pipeline update contained no EMA filing information. Research-grade 'SS-31' sold for laboratory use is unapproved material and is not FORZINITY.

07Research material and sourcing notes

Reported research-use reconstitution information

Not applicable to the approved product and not required. Per the FDA-approved FORZINITY prescribing information (regulatory source), the drug is supplied as a ready-to-use sterile, clear, colorless to yellow aqueous solution at 80 mg/mL in 3.5 mL single-patient-use vials for subcutaneous injection; no reconstitution step exists. Reconstitution protocols circulating for lyophilised 'SS-31' research powder (typically bacteriostatic water, gentle swirling) are vendor-derived, are not documented in peer-reviewed literature or in any regulatory document, and do not describe the approved product. No dosing guidance is given here.

Reported storage and stability information

From the FDA-approved FORZINITY prescribing information (regulatory source): store unopened vials refrigerated at 2°C to 8°C (36°F to 46°F). After the first dose is withdrawn, the opened vial may be kept either refrigerated at 2°C to 8°C or at room temperature 20°C to 25°C (68°F to 77°F). Discard the vial 8 days after first opening even if product remains. The label does not specify a light-protection requirement. Storage conditions for research-grade lyophilised SS-31 are vendor-derived and are not covered by this labelling.

Identity and sourcing notes

The single largest identity issue is form ambiguity. 'SS-31' and 'elamipretide' name the same peptide, but the approved medicine is a specific tris-hydrochloride salt in a specific ready-to-use aqueous formulation, whereas research-channel material is usually a lyophilised powder of unstated salt form (acetate and hydrochloride both circulate). A quoted molecular weight of 639.8 refers to the free base and 749.2 to the tris-hydrochloride; neither by itself tells you the net peptide content of a vial, and a vial labelled by gross mass of an acetate salt contains less peptide than the same gross mass of free base. Synthesis is non-trivial: Dmt (2',6'-dimethyltyrosine) is a specialty non-natural amino acid, the peptide is C-terminally amidated, and position 1 must be the D-enantiomer of arginine. Plausible failure modes are therefore D/L epimerisation at position 1, incomplete or absent C-terminal amidation, substitution of ordinary tyrosine for Dmt, and deletion sequences. A certificate of analysis can support net peptide content, gross purity by RP-HPLC, and mass confirmation by MS. It cannot by itself establish stereochemistry at position 1, cannot distinguish Dmt from an isobaric or near-isobaric alternative without orthogonal confirmation, and typically says nothing about endotoxin, residual solvents, or counterion identity unless those tests are explicitly reported. COAs supplied by the seller rather than an independent laboratory, or lacking an instrument trace and a batch number matching the vial, carry limited evidentiary weight. This is informational only and is not a recommendation to obtain or use unapproved material.

08References and evidence

Primary sources

1. The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipinprimary literatureBirk AV, Liu S, Soong Y, Mills W, Singh P, Warren JD, Seshan SV, Pardee JD, Szeto HH — Journal of the American Society of Nephrology, 2013;24(8):1250-1261
2. First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergeticsreviewSzeto HH — British Journal of Pharmacology, 2014
3. The mitochondria-targeted peptide SS-31 binds lipid bilayers and modulates surface electrostatics as a key component of its mechanism of actionprimary literatureMitchell W, Ng EA, Tamucci JD, Boyd KJ, Sathappa M, Coscia A, Pan M, Han X, Eddy NA, May ER, Szeto HH, Alder NN — Journal of Biological Chemistry, 2020;295(21):7452-7469
4. Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trialclinical trialKaraa A, Bertini E, Carelli V, et al. — Neurology, 2023 (PMID 37268435)
5. FORZINITY (elamipretide) injection, for subcutaneous use — Highlights of Prescribing Information, NDA 215244regulatoryUS Food and Drug Administration — FDA, 2025
6. Application Number 215244Orig1s000, Chemistry ReviewregulatoryUS Food and Drug Administration, Center for Drug Evaluation and Research — FDA, 2025
7. FDA Briefing Document, NDA 215244, Elamipretide (advisory committee materials)regulatoryUS Food and Drug Administration — FDA, 2024
8. SS-31 (also known as Elamipretide, Bendavia, MTP-131) — For ResearchersreviewAlzheimer's Drug Discovery Foundation, Cognitive Vitality — Cognitive Vitality Report, ADDF
9. Interventions with Potential to Mitigate Injection Site Reactions Following Subcutaneous Elamipretide Administration: A Phase 1, Crossover Studyclinical trialStealth BioTherapeutics investigators — Fortune Journals

Chemical and molecular databases

• PubChem CID 11764719 (Elamipretide)
• ChEMBL CHEMBL3833370 (Elamipretide)
• DrugBank DB11981 (Elamipretide)
• DailyMed — FORZINITY (elamipretide hydrochloride) label, UNII 87GWG91S09 / E40WZ3BK2D
• Stealth BioTherapeutics commercial and R&D pipeline update, January 2026
• Barth Syndrome Foundation — FDA approves first medication for Barth syndrome (19 September 2025)

09Related compounds

• MOTS-cA mitochondrial-derived peptide studied in the same mitochondrial-bioenergetics research space, though it is genomically encoded in mtDNA rather than a designed synthetic tetrapeptide.
• HumaninAnother mitochondrial-derived peptide frequently discussed alongside SS-31 in mitochondrial stress and cytoprotection literature.Reference page in preparation
• NAD+A mitochondrial redox cofactor targeted by a parallel strategy of restoring bioenergetic capacity rather than protecting membrane lipids.Reference page in preparation
• Methylene BlueAn alternative mitochondrial electron-transport-directed agent, acting as an electron cycler rather than a cardiolipin binder.Reference page in preparation
• GlutathioneThe principal endogenous mitochondrial and cytosolic antioxidant, and the comparator against which SS-31's non-antioxidant, cardiolipin-protective framing is usually contrasted.Reference page in preparation

10Frequently asked questions