Scientific Reference
SS-31 (Elamipretide)
Evidence profile: Human Phase 3 evidence
SS-31, also named elamipretide, is a synthetic tetrapeptide of alternating aromatic and basic residues that concentrates in mitochondria. Its sequence is D-Arg-Dmt-Lys-Phe-NH2, where Dmt is 2′,6′-dimethyltyrosine; the N-terminal D-amino acid slows enzymatic breakdown, and the peptide carries a net charge of +3 at neutral pH. The SS prefix refers to Szeto and Schiller, who described a series of related peptides that grew out of opioid peptide research, although SS-31 is reported to have no opioid activity. Most mechanistic work uses isolated mitochondria, cultured cells and rodent ischaemia models. It has also been tested in human clinical trials, chiefly in inherited mitochondrial disorders, and those data are smaller and less consistent than the preclinical literature.
Mechanism of Action
SS-31 crosses cell membranes despite its positive charge and has been reported to accumulate at the inner mitochondrial membrane. The favoured explanation is binding to cardiolipin, a phospholipid largely confined to that membrane, through electrostatic and hydrophobic contacts. Biophysical studies suggest this binding changes membrane surface charge and the way cytochrome c associates with cardiolipin, including cytochrome c's peroxidase activity. In isolated mitochondria and cell models, its effects on cristae structure, electron transport and reactive oxygen species have been examined. Early papers described it as a direct antioxidant via its dimethyltyrosine; later work puts more weight on cardiolipin.
Molecular Information
- Type: Aromatic-cationic tetrapeptide — mitochondria-targeted
- Length: 4 amino acids
- Molecular weight: 639.8 g/mol
- Molecular formula: C32H49N9O5
- CAS: 736992-21-5
Published Research
Long-term efficacy and safety of elamipretide in patients with Barth syndrome: 168-week open-label extension results of TAZPOWER
Thompson WR et al. · Genetics in medicine : official journal of the American College of Medical Genetics · 2024 · Clinical
PMID 38602181 — View on PubMedEfficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial
Karaa A et al. · Neurology · 2023 · Clinical
PMID 37268435 — View on PubMed