SS-31 (Elamipretide): The Four-Residue Peptide That Binds Cardiolipin

SS-31 is a four-residue peptide that its developers designed to sit in the inner membrane of mitochondria. It is also known as elamipretide, MTP-131 and Bendavia, and in September 2025 it received accelerated approval in the United States (Shirley 2026). This Vial Post explainer looks at the molecule itself: how four amino acids were chosen, what the binding studies showed about cardiolipin, and how the story moved from a 2004 cell-biology paper to a regulatory decision.

Nothing here is guidance on use in people or animals. The Vial Post covers SS-31 only as a subject of laboratory and literature research.

The Molecule in Four Residues

PubChem lists elamipretide under CID 11764719 (PubChem: Elamipretide):

• Sequence: D-Arg-Dmt-Lys-Phe-NH2, where Dmt is 2',6'-dimethyltyrosine.
• Formula and mass: C32H49N9O5, with a computed molecular weight of 639.8 g/mol.
• Other names: SS-31, MTP-131, Bendavia and "Szeto-Schiller peptide."
• A D-residue up front: PubChem's IUPAC name gives the arginine as (2R), the D-configuration. Dynamite Peptides explains the D/L system in its guide to D- vs L-amino acids.

The Design Rule: Alternate Aromatic and Basic

The founding 2004 paper from H. H. Szeto's group at Weill Cornell, with P. W. Schiller among the co-authors, laid out the design (Zhao 2004):

• The peptides are built on alternating aromatic and basic residues, with dimethyltyrosine supplying the radical-scavenging property.
• They are cell-permeable and concentrate 1000-fold in the inner mitochondrial membrane.
• In neuronal N2A cells they reduced intracellular reactive oxygen species and cell death caused by t-butylhydroperoxide, with EC50 values in the nanomolar range.
• In isolated mitochondria they reduced ROS production, inhibited permeability transition and swelling, and blocked calcium-induced cytochrome c release.
• The control experiment: analogs without dimethyltyrosine did not inhibit mitochondrial ROS or swelling.

Finding the Target: Cardiolipin

Nearly a decade later, Birk and colleagues asked what SS-31 actually binds. Using a polarity-sensitive fluorescent analog of the peptide, they showed it binds cardiolipin with high affinity (Birk 2013). Cardiolipin is an anionic phospholipid of the inner mitochondrial membrane that is required for cristae to form (Birk 2013). Two further findings from that paper:

• the SS-31/cardiolipin complex inhibited the peroxidase activity of cytochrome c, which catalyzes cardiolipin peroxidation, by protecting its heme iron;
• in a rat kidney ischemia model, pretreatment with SS-31 protected cristae membranes and prevented mitochondrial swelling.

Szeto's 2014 review in the *British Journal of Pharmacology* puts the mechanism in one line: SS-31 binds cardiolipin through electrostatic and hydrophobic interactions and so keeps cardiolipin from converting cytochrome c into a peroxidase, while leaving its electron-carrying role intact (Szeto 2014). The review describes cardiolipin as found only in the inner membrane, where it shapes the cristae and organizes respiratory complexes into supercomplexes (Szeto 2014).

From Bench Tool to Regulatory File

• 2004: the Szeto-Schiller peptide antioxidants are described (Zhao 2004).
• 2013: cardiolipin is identified as the binding partner; the authors note SS-31 was then in clinical trials (Birk 2013).
• 2014: the first cardiolipin-protective compound is reviewed alongside an update on its clinical program (Szeto 2014).
• September 2025: elamipretide, developed by Stealth BioTherapeutics and marketed as Forzinity, receives U.S. accelerated approval for Barth syndrome, an ultra-rare X-linked genetic disorder (Shirley 2026).

That approval covers one defined patient group and a regulated drug product. It says nothing about research-grade material, and this article does not describe any use of it.

Frequently Asked Questions

Is SS-31 the same thing as elamipretide? Yes. PubChem lists SS-31, MTP-131 and Bendavia as synonyms of elamipretide (PubChem: Elamipretide).

Why the dimethyltyrosine? In the 2004 study it supplied the scavenging property: analogs without it did not inhibit mitochondrial ROS generation or swelling (Zhao 2004).

What mass should a COA show? PubChem's computed molecular weight is 639.8 g/mol for C32H49N9O5 (PubChem: Elamipretide). Mass spectrometry should match the stated form. Our explainer on HPLC versus mass spec covers what each test can and cannot show.

For research and educational use only. This article is not medical advice and does not describe dosing or human use.