DRPSHP

Scientific Reference

SS-31

Evidence profile: Human Phase 3 evidence

SS-31, known clinically as elamipretide, is a four-residue peptide built to home in on mitochondria. Its sequence is D-Arg-Dmt-Lys-Phe-NH2, where Dmt stands for 2',6'-dimethyltyrosine. A D-amino acid at the front resists enzymatic breakdown, and at neutral pH the molecule has a net charge of +3. The SS label honours Szeto and Schiller, whose group derived a family of such peptides from opioid chemistry, although SS-31 itself is described as lacking opioid activity. Mechanistic work mostly uses isolated mitochondria, cell lines and rodent models of ischaemia. Human trials exist, particularly in inherited mitochondrial disease, but they are smaller and less uniform than the preclinical data.

Mechanism of Action

Despite its positive charge the peptide enters cells and is reported to concentrate on the inner mitochondrial membrane, probably through contact with cardiolipin, a phospholipid largely restricted to that membrane. Biophysical experiments indicate the contact alters membrane surface charge and how cytochrome c sits against cardiolipin, including cytochrome c peroxidase activity. Downstream readouts studied include cristae architecture, electron transport and reactive oxygen species. Early reports credited the dimethyltyrosine with direct antioxidant action; more recent interpretations lean towards cardiolipin.

Molecular Information

  • Type: Aromatic-cationic tetrapeptide, mitochondria-targeted
  • 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 PubMed

  • Efficacy 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