Peerless Peptides

SS-31

Synthetic mitochondria-targeted cardiolipin-binding tetrapeptide, D-Arg-Dmt-Lys-Phe-NH2 (elamipretide; Bendavia; MTP-131)

SS-31 is the synthetic four-residue mitochondria-targeted peptide H-D-Arg-Dmt-Lys-Phe-NH2, where Dmt is 2',6'-dimethyltyrosine (non-natural) and D-Arg is the D-enantiomer of arginine. The compound was discovered in 2004 in the laboratory of Hazel H. Szeto at Weill Cornell Medicine with chemistry collaborator Peter W. Schiller of the Clinical Research Institute of Montreal. The active pharmaceutical ingredient elamipretide hydrochloride was granted FDA accelerated approval September 19, 2025 (Forzinity, NDA 215244, Stealth BioTherapeutics) for Barth syndrome in patients weighing at least 30 kg, the first mitochondria-targeted peptide drug approved by the FDA.

Available for laboratory research use only.

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Biochemical Profile

CAS Number
736992-21-5 (free base); 72244098-12-0 (hydrochloride)
Molecular Formula
C32H49N9O5
Molecular Weight
639.80 g/mol (free base)
Purity
≥99% (HPLC-UV (220 nm with confirmatory 280 nm))
PubChem CID
11764719
Amino Acid Sequence
H-D-Arg-Dmt-Lys-Phe-NH2 (D-Arg at position 1 and 2',6'-dimethyltyrosine at position 2 are non-natural; the alternating cationic-aromatic motif is the SS-peptide signature)

Cardiolipin Binding and Mitochondrial Surface Electrostatics

SS-31 binds to cardiolipin, an anionic diacyl phospholipid expressed exclusively on the inner leaflet of the inner mitochondrial membrane. Cardiolipin organizes electron-transport-chain complexes I, III, and IV into the supercomplexes that support efficient oxidative phosphorylation. The Birk et al. 2013 paper in the Szeto laboratory established the cardiolipin-binding model in a rat renal-ischemia preparation, reporting that SS-31 binding prevented cardiolipin peroxidation, preserved cristae architecture, restored ATP synthesis, and reduced reactive-oxygen-species output[1].

The peptide carries two non-natural residues that are load-bearing for the chemistry. D-arginine at position 1 confers exopeptidase resistance through the D-enantiomer configuration. The 2',6'-dimethyltyrosine (Dmt) at position 2 is the scavenging moiety: Zhao et al. 2004 demonstrated in the foundational SS-peptide paper that analogs lacking Dmt did not inhibit mitochondrial ROS generation, identifying the dimethyltyrosine ring as the active chemistry[2]. The alternating cationic-aromatic motif (D-Arg, Dmt, Lys, Phe) carries a net +3 charge at physiological pH yet concentrates approximately 1,000-fold in the inner mitochondrial membrane, a feature that distinguishes SS-31 from triphenylphosphonium-tagged agents whose uptake depends on membrane potential.

Mitchell et al. 2020, working at the University of Connecticut independently of the Szeto group, tested whether the binding was specific to cardiolipin's molecular structure or to its anionic charge[3]. Using systematic lipid-bilayer experiments, the authors reported that SS-31 binding depends on anionic surface charge density rather than specific recognition of the cardiolipin headgroup. SS-31 bound cardiolipin variants with approximately twice the affinity of phosphatidylglycerol, but the difference reflected charge density rather than specific molecular recognition. The peptide produced saturable alterations in lipid packing and reduced membrane surface potential without disrupting bilayer structure. The clinical hypothesis (binding cardiolipin stabilizes the supercomplexes of the inner mitochondrial membrane) survives the refinement; the molecular specificity is broader than originally framed.

A central methodological point: SS-31 has not been characterized as a conventional free-radical scavenger. The 2004 and 2013 papers were explicit that the compound has not been reported to function the way vitamin E or N-acetylcysteine functions. By stabilizing cardiolipin and preserving cristae architecture, the published data report that SS-31 reduces the electron leak that generates ROS in the first place. A 2020 PNAS paper used cross-linking mass spectrometry to map SS-31's interaction landscape across the inner mitochondrial proteome, extending the model: SS-31 contacts proteins that themselves bind cardiolipin (electron-transport-chain subunits, ATP synthase, adenine nucleotide translocator) and that depend on cardiolipin for stability.

Research Applications

Barth Syndrome — The Approved Indication

Barth syndrome is a rare X-linked recessive disorder caused by loss-of-function mutations in TAZ (tafazzin), an enzyme required for the remodeling of nascent cardiolipin into the mature tetra-linoleoyl form. The result is cardiolipin deficiency, mitochondrial cristae disorganization, cardiomyopathy, skeletal-muscle weakness, neutropenia, growth delay, and reduced life expectancy. Approximately 150 patients are diagnosed in the United States; the disease affects predominantly males. The mechanistic fit between SS-31 (which binds cardiolipin) and Barth syndrome (a disease of cardiolipin deficiency) is the cleanest mechanism-to-indication mapping in the entire elamipretide program.

The pivotal TAZPOWER trial (NCT03098797) enrolled 12 male patients in a randomized double-blind placebo-controlled crossover design with 12 weeks of elamipretide versus placebo, followed by an open-label extension that reached week 168. Part 1 primary endpoints (6-minute walk test distance and BTHS-SA total fatigue score) were both missed in the randomized phase. The open-label extension (Thompson et al. 2024) reported sustained improvements from open-label baseline on knee-extensor muscle strength, 6MWT, fatigue scores, and cardiac stroke-volume measures[4]. Knee-extensor muscle strength improvement of approximately 45% from open-label baseline became the intermediate clinical endpoint on which the FDA accelerated approval was granted.

Cardiac and Cardiovascular Research

Cardiac ischemia-reperfusion preparations have been a major focus of the SS-31 preclinical literature. The original Szeto group reported reductions in myocardial infarct size in rat coronary-occlusion models (Cho et al. 2007)[5]. The independent laboratory of Hani Sabbah at Henry Ford Hospital reported that long-term elamipretide administration normalized mitochondrial dynamics and improved cardiac function readouts in canine heart-failure models, a critical replication outside the Szeto research orbit.

The preclinical cardiac evidence supported two large randomized clinical trials. EMBRACE-STEMI (NCT01572909) was a Phase 2a trial in approximately 297 patients with anterior ST-elevation myocardial infarction receiving primary percutaneous coronary intervention. The primary endpoint of integrated serum CK-MB area-under-the-curve as a measure of infarct size was missed; elamipretide was not associated with a reduction in CK-MB AUC versus placebo[6]. PROGRESS-HF (NCT02788747) was a Phase 2 trial in 71 patients with stable heart failure with reduced ejection fraction, with daily subcutaneous elamipretide at two doses (4 mg and 40 mg) versus placebo for 4 weeks. The primary endpoint of change in left-ventricular end-systolic volume by cardiac MRI from baseline to week 4 was missed; Daubert et al. 2020 reported no significant difference between either elamipretide dose and placebo[7]. No FDA-approved cardiac indication exists for elamipretide.

Dry AMD and Ophthalmic Research

The retinal pigment epithelium and photoreceptor layers carry extraordinarily high mitochondrial densities. Preclinical work in aging and oxidative-stress models of retinal degeneration reported that SS-31 preserves photoreceptor mitochondrial function in rodent preparations, providing the rationale for the ReCLAIM Phase 1 and ReCLAIM-2 Phase 2 clinical program in dry age-related macular degeneration with geographic atrophy.

ReCLAIM-2 (NCT03891875) was a prospective Phase 2 randomized placebo-controlled double-masked multicenter trial in 176 patients aged 55 and older with one or more eyes with dry AMD and geographic atrophy (117 elamipretide, 59 placebo, randomized 2:1). Daily subcutaneous elamipretide 40 mg was administered for 48 weeks. Co-primary endpoints were mean change from baseline in low-luminance best-corrected visual acuity and mean change in square-root-transformed geographic-atrophy area on OCT. Both primary endpoints were missed at week 48 (Stealth topline May 2022; full publication Allingham et al. 2024)[8]. A prespecified secondary endpoint, change in macular ellipsoid-zone attenuation/loss, reported a 43% reduction in elamipretide-treated eyes versus placebo. Stealth subsequently advanced ReNEW (Phase 3, approximately 360 patients, 96 weeks) with the ellipsoid-zone secondary endpoint repositioned as the primary. ReNEW is ongoing as of May 2026.

Primary Mitochondrial Myopathy Research

Skeletal-muscle mitochondrial dysfunction has been investigated in the SS-31 preclinical literature, with the Marcinek group at the University of Washington publishing extensively on age-related mitochondrial dysfunction in aged-mouse skeletal muscle. Together with primary-mitochondrial-myopathy preclinical models, this body of work formed the rationale for the MMPOWER clinical program.

MMPOWER-3 (NCT03323749) was a Phase 3 randomized double-blind placebo-controlled trial in 218 patients with genetically confirmed primary mitochondrial myopathy aged 16-80, with subcutaneous elamipretide (the trial registry protocol specified 40 mg once-daily injection) versus placebo for 24 weeks. Co-primary endpoints were change in distance walked on the 6-minute walk test and change in total fatigue score on the Primary Mitochondrial Myopathy Symptom Assessment. Both primary endpoints were missed: least-squares mean differences from baseline to week 24 were 6MWT minus 3.2 meters and PMMSA TFS minus 0.07 points (Karaa et al. 2023)[9]. A prespecified subgroup of patients with nuclear-DNA pathogenic variants (a minority of the trial population) reported improvement on 6MWT; the mitochondrial-DNA subgroup did not differ from placebo. The genotype-stratified post-hoc analysis motivated the NuPOWER Phase 3 trial (NCT05162768) in nDNA-restricted PMM, which is fully enrolled with results pending.

Cardiolipin Biochemistry and Bilayer Mechanism

Cardiolipin is the signature anionic phospholipid of the inner mitochondrial membrane. It carries four acyl chains (rather than the two of standard phospholipids) and a net negative charge that contributes to the strongly anionic surface of the inner mitochondrial membrane. Cardiolipin organizes electron-transport-chain complexes into supercomplexes, modulates the activity of ATP synthase and the adenine nucleotide translocator, and undergoes peroxidation under oxidative stress, an event that initiates release of cytochrome c and apoptosis.

The Birk et al. 2013 paper established the cardiolipin-binding model for SS-31 in rat renal-ischemia preparations[1]. The Mitchell et al. 2020 paper at the University of Connecticut refined the mechanism using lipid-bilayer systems, reporting that SS-31 binding depends on overall anionic surface charge density rather than specific molecular recognition of the cardiolipin headgroup[3]. SS-31 bound cardiolipin variants with approximately twice the affinity of phosphatidylglycerol but the difference reflected charge density rather than specific recognition. A 2020 PNAS paper from the Bruce laboratory at the University of Washington used cross-linking mass spectrometry to map SS-31's interaction landscape across the inner mitochondrial proteome, extending the model: SS-31 contacts proteins that themselves bind cardiolipin and that depend on cardiolipin for stability[10]. The biochemistry across these independent laboratories has converged on an aromatic-cationic peptide that acts as an electrostatic-charge modulator preferential for anionic mitochondrial membranes.

Approved-Drug Context and the Replication Record

The September 19, 2025 FDA accelerated approval of Forzinity (elamipretide HCl injection, NDA 215244, Stealth BioTherapeutics) made elamipretide the first mitochondria-targeted peptide drug approved by the FDA[11]. The approved indication is narrow: Barth syndrome in adult and pediatric patients weighing at least 30 kg, with continued approval contingent on a confirmatory trial verifying clinical benefit and a commitment to collect data in patients under 30 kg. The regulatory pathway was contested. The first NDA submission was returned by FDA Refuse-to-File on October 18, 2021. The second submission (January 29, 2024) was accepted for standard review, granted Priority Review May 6, 2024, voted favorably at the Cardiovascular and Renal Drugs Advisory Committee on October 10, 2024, received a Complete Response Letter in May 2025 citing manufacturing CGMP observations at a third-party facility (not efficacy or safety concerns about elamipretide itself), was resubmitted as a Class 2 response August 15, 2025, and was approved September 19, 2025.

The regulatory approval rests on a small pivotal trial (TAZPOWER, n=12 crossover with open-label extension) and an intermediate clinical endpoint (knee-extensor muscle strength). Across the four largest-N Phase 2/3 trials of elamipretide (EMBRACE-STEMI approximately 297 patients, PROGRESS-HF 71, ReCLAIM-2 176, MMPOWER-3 218), every prespecified primary endpoint was missed. The aggregate pattern raises a methodology question that applies across mitochondrial-disease drug development: whether the standard outcome measures (6-minute walk test, fatigue scales, geographic-atrophy area, left-ventricular end-systolic volume) are sensitive enough to detect a real biological effect in clinically and genetically heterogeneous patient populations. The MMPOWER-3 to NuPOWER pivot (genotype enrichment) and the ReCLAIM-2 to ReNEW pivot (secondary endpoint repositioned as primary) represent the standard methodological response: when the heterogeneous-population trial misses, enrich the population or shift the outcome measure to the responsive signal.

Reconstitution & Storage

Recommended Diluent
Bacteriostatic water (0.9% benzyl alcohol) or sterile saline
Storage (lyophilized)
-20°C, dry, dark, 24+ months
Storage (reconstituted)
2-8°C, use within 28 days
Shelf Life
24+ months lyophilized; 12-18 months at 4°C

Research References

  1. [1] Birk AV, Liu S, Soong Y, et al. The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin. J Am Soc Nephrol. 2013;24(8):1250-1261. PMID:23813215
  2. [2] Zhao K, Zhao G-M, Wu D, Soong Y, Birk AV, Schiller PW, Szeto HH. Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury. J Biol Chem. 2004;279(33):34682-34690. PMID:15178689
  3. [3] Mitchell W, Ng EA, Tamucci JD, et al. The mitochondria-targeted peptide SS-31 binds lipid bilayers and modulates surface electrostatics as a key component of its mechanism of action. J Biol Chem. 2020;295(21):7452-7469. PMID:32253237
  4. [4] Thompson WR, Manuel R, Abbruscato A, et al. Long-term efficacy and safety of elamipretide in patients with Barth syndrome: 168-week open-label extension results of TAZPOWER. Genet Med. 2024;26(7):101138. PMID:38602181
  5. [5] Cho J, Won K, Wu D, Soong Y, Liu S, Szeto HH, Hong MK. Potent mitochondria-targeted peptides reduce myocardial infarction in rats. Coron Artery Dis. 2007;18(3):215-220. PMID:17429296
  6. [6] Gibson CM, Giugliano RP, Kloner RA, et al. EMBRACE STEMI study: a Phase 2a trial to evaluate the safety, tolerability, and efficacy of intravenous MTP-131 on reperfusion injury in patients undergoing primary percutaneous coronary intervention. Eur Heart J. 2016;37(16):1296-1304. PMID:26586786
  7. [7] Daubert MA, Yow E, Dunn G, et al. Novel mitochondria-targeting peptide in heart failure treatment: a randomized, placebo-controlled Phase 2 trial of elamipretide. Circ Heart Fail. 2017;10(12):e004389. (PROGRESS-HF Phase 2 readout) PMID:32068002
  8. [8] Allingham MJ, Mettu PS, Cousins SW. Elamipretide, a mitochondrial-targeted drug, for the treatment of vision loss in dry AMD with non-central geographic atrophy: results of the Phase 2 ReCLAIM-2 clinical trial. Ophthalmol Sci. 2024;4(6):100586. PMID:39605874
  9. [9] Karaa A, Bertini E, Carelli V, et al. Efficacy and safety of elamipretide in individuals with primary mitochondrial myopathy: the MMPOWER-3 randomized clinical trial. Neurology. 2023;101(3):e238-e252. PMID:37268435
  10. [10] Chavez JD, Tang X, Campbell MD, et al. Mitochondrial protein interaction landscape of SS-31. Proc Natl Acad Sci USA. 2020;117(26):15363-15373. PMID:32554501
  11. [11] U.S. Food and Drug Administration. Forzinity (elamipretide hydrochloride injection) prescribing information, NDA 215244. Accelerated approval September 19, 2025. Indicated for the treatment of Barth syndrome in adult and pediatric patients weighing at least 30 kg.
  12. [12] Szeto HH, Schiller PW. Novel therapies targeting inner mitochondrial membrane: from discovery to clinical development. Pharm Res. 2011;28(11):2669-2679. PMID:21638136
  13. [13] Szeto HH, Birk AV. Serendipity and the discovery of novel compounds that restore mitochondrial plasticity. Clin Pharmacol Ther. 2014;96(6):672-683. PMID:25188725
  14. [14] Sabbah HN, Gupta RC, Kohli S, Wang M, Hachem S, Zhang K. Chronic therapy with elamipretide (MTP-131), a novel mitochondria-targeting peptide, improves left ventricular and mitochondrial function in dogs with advanced heart failure. Circ Heart Fail. 2016;9(2):e002206. PMID:26839394
  15. [15] Karaa A, Haas R, Goldstein A, Vockley J, Cohen BH. A randomized crossover trial of elamipretide in adults with primary mitochondrial myopathy: post-hoc analysis of genotype-stratified outcomes from MMPOWER-3. Orphanet J Rare Dis. 2024. PMID:39563391
  16. [16] Reid Thompson W, DeCost G, Jeyaraju DV, et al. Elamipretide in Barth syndrome: a review of structure, mechanism, and therapeutic potential. Int J Mol Sci. 2025;26(3):944. PMID:39940715

Scientific Journal Author

Hazel H. Szeto, MD, PhD

Department of Pharmacology, Weill Cornell Medicine (originating researcher of the SS-peptide family; co-founder of Stealth BioTherapeutics, 2006)

Landmark Publications

  • Zhao K, Zhao G-M, Wu D, Soong Y, Birk AV, Schiller PW, Szeto HH. Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury. J Biol Chem. 2004;279(33):34682-34690. (PMID 15178689)
  • Birk AV, Liu S, Soong Y, et al. The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin. J Am Soc Nephrol. 2013;24(8):1250-1261. (PMID 23813215)
  • Szeto HH, Birk AV. Serendipity and the discovery of novel compounds that restore mitochondrial plasticity. Clin Pharmacol Ther. 2014;96(6):672-683. (PMID 25188725)

Dr. Szeto is independently cited here as the originating researcher of the SS (Szeto-Schiller) mitochondria-targeted peptide family at Weill Cornell Medicine. There is no affiliation or commercial relationship between Dr. Szeto, Weill Cornell Medicine, Stealth BioTherapeutics, or any associated commercial entity, and Peerless Peptides.

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