SS-31 50mg (with Bacteriostatic Water)

SS-31 (also known as elamipretide, bendavia, and MTP-131) is a synthetic aromatic-cationic tetrapeptide with the sequence D-Arg-2',6'-dimethyltyrosine-Lys-Phe-NH2. The molecule was developed in the early 2000s by Hazel Szeto's laboratory at Weill Cornell Medical College as part of a structured medicinal-chemistry program — the Szeto-Schiller (SS) peptides — designed to identify mitochondria-targeted cell-permeable peptides for the study of mitochondrial dysfunction. SS-31 emerged from this program as a compound that selectively concentrates in the inner mitochondrial membrane by binding the unique mitochondrial phospholipid cardiolipin.

The mechanism by which SS-31 reaches its mitochondrial target is distinctive. Most mitochondrial-targeting strategies rely on triphenylphosphonium (TPP+) cation conjugation to drive electrophoretic uptake driven by the mitochondrial membrane potential. SS-31 instead uses an inherent aromatic-cationic charge distribution that enables passive cellular uptake and, once inside the cell, high-affinity binding to cardiolipin in the inner mitochondrial membrane. Cardiolipin is a four-acyl-chain phospholipid uniquely abundant in the inner mitochondrial membrane and required for the proper organization of the electron transport chain complexes and the formation of mitochondrial cristae. SS-31 binding stabilizes cardiolipin, preserves cristae structure, and supports electron-transport-chain assembly and function under stress conditions.

SS-31 (as elamipretide) has been investigated in clinical-research programs through Stealth BioTherapeutics in indications including primary mitochondrial myopathy, Barth syndrome, geographic atrophy in age-related macular degeneration, and Leber hereditary optic neuropathy. The clinical-research record is published; the molecule has not received approval from major Western regulatory agencies for any indication as of this writing.

This page is a research-only educational reference. SS-31 supplied as a research peptide is intended for laboratory and analytical work; no therapeutic or human-use claims are made.

SS-31 is a four-residue synthetic peptide with an alternating aromatic-cationic structure (D-Arg-Dmt-Lys-Phe-NH2). The aromatic residues (2',6'-dimethyltyrosine at position 2 and phenylalanine at position 4) provide hydrophobic membrane-interaction surfaces; the basic residues (D-arginine at position 1 and lysine at position 3) provide cationic charge. The D-amino acid at position 1 confers protease resistance, and the C-terminal amidation removes the C-terminal carboxylate. The molecule is small, water-soluble at physiological pH, and cell-permeable.

The biological target of SS-31 is cardiolipin in the inner mitochondrial membrane. Cardiolipin is a unique four-acyl-chain phospholipid synthesized in the inner mitochondrial membrane and required for: proper assembly and function of the electron transport chain complexes (particularly Complex I, III, IV, and the F1F0-ATP synthase); supercomplex organization of the respiratory chain; cristae membrane curvature and structure; and the regulation of cytochrome c at the outer leaflet of the inner membrane (where cardiolipin-bound cytochrome c is the substrate for cardiolipin peroxidation that initiates apoptotic release). SS-31 binds cardiolipin through electrostatic interaction with the cardiolipin headgroup and aromatic insertion into the acyl-chain interface, with high selectivity for cardiolipin over other mitochondrial phospholipids.

The functional consequences of SS-31 binding cardiolipin are several. SS-31 stabilizes the cardiolipin/cytochrome c interaction in a configuration that preserves cytochrome c's electron-carrier activity while suppressing its peroxidase activity (which is implicated in cardiolipin peroxidation, mitochondrial permeability transition, and apoptosis initiation). SS-31 also preserves cristae structure under stress conditions in published electron-microscopy and bioenergetics studies. The net effect in mitochondrial-dysfunction research models is improved respiratory function, reduced ROS production, preserved ATP synthesis, and reduced apoptotic signaling.

It is important to be clear about what SS-31 is not. It is not an antioxidant in the classical small-molecule free-radical-scavenger sense — although the molecule reduces mitochondrial ROS production in research models, the principal mechanism is preservation of mitochondrial structure and function, not direct chemical scavenging of radicals. It is not an approved medicine in the major Western jurisdictions as of this writing, despite extensive clinical-research investigation under the name elamipretide. And it is not a "longevity drug" in the lay sense; its published research role is in mitochondrial dysfunction, ischemia-reperfusion injury, and specific mitochondrial disease contexts.

The Szeto-Schiller peptide program at Weill Cornell Medical College began in the late 1990s as a structured medicinal-chemistry effort to identify cell-permeable peptides with selective mitochondrial accumulation. Hazel Szeto and Peter Schiller designed a series of small aromatic-cationic peptides (SS-01, SS-02, SS-19, SS-20, SS-31, and others) and screened them for cellular uptake, mitochondrial accumulation, and cytoprotective activity in models of oxidative stress. SS-31 emerged as the lead compound with favorable uptake, mitochondrial targeting, and cardiolipin-binding properties.

The early SS peptide work was published in the early 2000s and characterized the mitochondrial accumulation (driven by cardiolipin binding, not by membrane-potential-driven uptake) and the cytoprotective effects in cell-culture models of oxidative stress. Through the mid-2000s, SS-31 was investigated in animal models of ischemia-reperfusion injury (cardiac, renal, and cerebral), of doxorubicin cardiotoxicity, and of various other mitochondrial-dysfunction contexts. The published preclinical literature established SS-31 as a tool reagent for the study of cardiolipin biology and mitochondrial structural preservation.

Stealth BioTherapeutics (originally Stealth Peptides) was founded around the SS-31 program to develop the molecule as a therapy under the name elamipretide (formerly bendavia, MTP-131). The clinical-research program over the 2010s included Phase 2 and Phase 3 trials in primary mitochondrial myopathy (the MMPOWER and MMPOWER-3 trials), Barth syndrome (a rare X-linked cardiomyopathy caused by mutations in tafazzin, a cardiolipin-remodeling enzyme), geographic atrophy in age-related macular degeneration (the ReCLAIM trials), and Leber hereditary optic neuropathy. The clinical results have been mixed: in some endpoints and indications elamipretide produced statistically meaningful effects, in others it did not, and as of this writing the molecule has not received approval from the US FDA, EMA, or other major Western agencies.

A separate and substantial preclinical-research literature continues to use SS-31 as a tool reagent for cardiolipin and cristae biology research. The molecule has been used in published studies of mitochondrial aging, heart-failure pathophysiology, kidney ischemic injury, neurodegenerative disease, and basic cardiolipin biology. The cardiolipin-binding mechanism and the consequences for respiratory chain organization, cristae structure, and cytochrome c handling remain active areas of mitochondrial-biology research.

The broader mitochondria-targeted therapeutics field has also continued to evolve. The TPP+-conjugated antioxidant MitoQ is one alternative approach; mitochondria-targeted peroxidase mimetics, cardiolipin remodeling modulators, and other approaches form the broader landscape within which SS-31's distinct cardiolipin-binding mechanism is positioned.

The inner mitochondrial membrane is the site of oxidative phosphorylation — the coupled process by which the electron transport chain (ETC) generates a transmembrane proton gradient and the F1F0-ATP synthase uses that gradient to synthesize ATP. The proper function of this machinery requires the highly folded cristae topology of the inner membrane, the supercomplex assembly of ETC complexes (Complex I, III, IV organized into respirasomes), and the unique lipid environment provided by cardiolipin.

Cardiolipin is a four-acyl-chain phospholipid synthesized in the inner mitochondrial membrane by a multistep pathway involving phosphatidylglycerol, cardiolipin synthase, and the remodeling enzyme tafazzin (mutations in tafazzin cause Barth syndrome). Cardiolipin constitutes roughly 15-20% of inner mitochondrial membrane phospholipid. It plays multiple essential roles: it binds and organizes ETC complexes (particularly Complex I, III, IV, and ATP synthase) into functional supercomplexes; it stabilizes the curved cristae membrane; and it provides the binding surface for cytochrome c at the outer leaflet of the inner membrane.

Cytochrome c is a peripheral inner-membrane protein that serves two functions. In its primary role, it shuttles electrons from Complex III to Complex IV in the ETC. In a secondary role, when cardiolipin is peroxidized (oxidatively damaged), cytochrome c acquires peroxidase activity that further peroxidizes cardiolipin and ultimately drives release of cytochrome c into the cytoplasm — a key step in intrinsic apoptosis. The cardiolipin-cytochrome c interaction is therefore a hinge point between mitochondrial energy production and mitochondrial-mediated cell death.

SS-31 binds cardiolipin in the inner mitochondrial membrane with high affinity and selectivity over other phospholipids. The binding produces several functional consequences:

First, SS-31 stabilizes the cristae membrane structure. Electron-microscopy studies in mitochondrial-dysfunction models show that SS-31 treatment preserves cristae morphology that would otherwise be disrupted by stress, ischemic injury, or disease processes.

Second, SS-31 supports ETC supercomplex assembly and function. Respirometry and complex-activity assays show that SS-31 preserves respiratory function under stress conditions, consistent with preservation of the cardiolipin-organized supercomplex architecture.

Third, SS-31 modifies the cardiolipin-cytochrome c interaction in a way that preserves cytochrome c's electron-carrier activity while suppressing its peroxidase activity. The net effect is reduced cardiolipin peroxidation, reduced ROS amplification, and reduced apoptotic signaling.

Fourth, by preserving mitochondrial structure and function, SS-31 reduces total mitochondrial ROS production. This is the basis for the molecule's frequent description as an "antioxidant," but the mechanism is structural-functional preservation rather than direct radical scavenging — an important distinction for interpreting research findings.

In published research, SS-31 has been studied in ischemia-reperfusion (cardiac, renal, cerebral), in aging-mitochondrial-dysfunction models, in heart-failure models, in Barth-syndrome cell and animal models, in retinal degeneration models, and in various other contexts where mitochondrial structural and functional preservation is a research focus.

SS-31 is a synthetic tetrapeptide with the sequence D-Arg-Dmt-Lys-Phe-NH2 (where Dmt is 2',6'-dimethyltyrosine, a non-proteinogenic aromatic amino acid). The molecular formula is C32H49N9O5 and the molecular weight is approximately 639.8 g/mol. The molecule contains two non-proteinogenic features: the D-arginine at position 1 (protease-resistance and altered cation positioning) and the dimethyltyrosine at position 2 (modified aromatic surface). The C-terminal amidation removes the terminal carboxylate.

The alternating aromatic-cationic structure (cationic D-Arg, aromatic Dmt, cationic Lys, aromatic Phe) is the structural feature that gives the molecule its unusual cellular uptake and mitochondrial-targeting properties. The cationic residues provide electrostatic interaction with the cardiolipin headgroup phosphates; the aromatic residues provide hydrophobic insertion into the acyl-chain interface. The combination produces high-affinity, selective cardiolipin binding.

Research-grade SS-31 is produced by standard solid-phase peptide synthesis (SPPS), with the non-proteinogenic dimethyltyrosine residue introduced as the appropriately protected Fmoc-Dmt-OH building block. The crude product is purified by reversed-phase HPLC to ≥98% purity for research use and verified by analytical HPLC and mass spectrometry. The peptide is supplied as a lyophilized powder, typically as the acetate or trifluoroacetate salt, and is reconstituted in sterile aqueous buffer for laboratory work. It is stable at -20 °C or below in the lyophilized form.

In published mitochondrial-biology research, SS-31 has been used in several principal applications:

Ischemia-reperfusion injury. Ex-vivo and in-vivo rodent cardiac, renal, and cerebral ischemia-reperfusion models are studied with SS-31 to investigate mitochondrial preservation as a strategy for reducing reperfusion injury. The published literature reports reduced infarct/lesion size, preserved tissue function, and reduced apoptotic cell death with SS-31 treatment in these models.

Heart failure and cardiac aging. Models of pressure-overload heart failure, doxorubicin cardiotoxicity, and aging-related cardiac mitochondrial dysfunction have been studied with SS-31 to investigate preservation of cardiac mitochondrial function.

Barth syndrome. Cell and animal models of tafazzin deficiency (the genetic cause of Barth syndrome) show abnormal cardiolipin remodeling and mitochondrial dysfunction. SS-31 has been studied in these models to investigate whether the cardiolipin-binding stabilization compensates for the defective remodeling.

Aging and mitochondrial dysfunction. Aged rodent skeletal muscle, brain, and other tissues show progressive mitochondrial dysfunction; SS-31 has been used in published research to investigate preservation of mitochondrial function in aged tissues.

Retinal degeneration. Models of age-related macular degeneration and Leber hereditary optic neuropathy have been studied with SS-31 (and clinically with elamipretide) to investigate retinal mitochondrial preservation.

Cardiolipin and cristae biology. SS-31 is a tool reagent for cardiolipin-binding studies, ETC supercomplex assembly studies, and cristae-morphology investigations. The molecule's cardiolipin-binding mechanism makes it useful as a pharmacological probe of cardiolipin-dependent mitochondrial biology.

Cell-culture mitochondrial-stress models. SS-31 is used in cultured cells subjected to oxidative stress, hypoxia, doxorubicin, or other mitochondrial insults to investigate cytoprotection and to characterize cardiolipin-binding-dependent versus -independent effects.

All applications are research-context. Nothing on this page describes a clinical protocol, dose, or therapy for human use outside an investigational research framework.

SS-31 sits within the broader landscape of mitochondria-targeted therapeutic candidates and research tools.

SS-31 (elamipretide, formerly bendavia / MTP-131) is a synthetic aromatic-cationic tetrapeptide developed in the early 2000s by Hazel Szeto's laboratory at Weill Cornell. The molecule reaches the inner mitochondrial membrane by passive cellular uptake followed by high-affinity binding to cardiolipin, the unique mitochondrial phospholipid required for electron transport chain supercomplex assembly and cristae structure. SS-31 binding stabilizes cardiolipin, preserves cristae morphology, supports ETC function under stress, and modifies the cardiolipin-cytochrome c interaction in a way that reduces apoptotic signaling and ROS production.

The molecule has been investigated in clinical-research programs as elamipretide in primary mitochondrial myopathy, Barth syndrome, geographic atrophy in age-related macular degeneration, and Leber hereditary optic neuropathy. Clinical results have been mixed; no major Western regulatory approval has resulted as of this writing. A substantial preclinical-research literature uses SS-31 as a tool reagent for cardiolipin biology, ETC supercomplex assembly, and mitochondrial structural preservation in ischemia-reperfusion, heart-failure, and aging-mitochondrial-dysfunction contexts.

This page is research educational only. SS-31 supplied as a research peptide is intended for laboratory and analytical work; no therapeutic or human-use claims are made.