SS-31research overview.

Overview

SS-31 is one of the Szeto-Schiller (SS) peptides, a series of short synthetic peptides built from alternating aromatic and basic residues ¹. Its non-proprietary name is elamipretide, and clinical papers also use the code MTP-131 ⁴.

Zhao et al. (2004) described the SS peptides as cell-permeable and reported that they concentrated about 1000-fold at the inner mitochondrial membrane ¹. Later work linked SS-31 to cardiolipin, a phospholipid found almost only in that membrane ^2,3.

The research falls into two broad stages: mechanistic studies in isolated mitochondria, cells and rodents ^1,2,3, and a clinical programme of randomised trials in adults with primary mitochondrial myopathy ^4,5,6,7.

Structure and chemistry

D-Arg-Dmt-Lys-Phe-NH₂. Molecular formula C32H49N9O5, molecular weight 639.8 g/mol, CAS 736992-21-5. Dmt is 2′,6′-dimethyl-L-tyrosine, a non-coded amino acid.

Three features define the design. The N-terminal residue is D-arginine, which, with the C-terminal amide, is expected to slow breakdown by common peptidases. Arginine and lysine give the peptide a net charge of +3 at neutral pH, while Dmt and phenylalanine supply the two aromatic rings. Zhao et al. describe this alternating aromatic-cationic motif as the basis of cell permeability, and the Dmt residue as the source of its radical-scavenging chemistry ¹.

Birk et al. (2013) used a fluorescent analogue of SS-31 to show high-affinity binding to cardiolipin, an anionic phospholipid required for the folded cristae of the inner membrane ².

Mechanisms investigated

Most mechanistic work comes from the group that developed the SS peptides at Weill Cornell Medical College ^1,2,3.

• Mitochondrial membrane targeting. In neuronal N2A cells and isolated mitochondria, Zhao et al. (2004) reported reduced reactive oxygen species, inhibition of the mitochondrial permeability transition and swelling, and less cytochrome c release ¹.
• Cardiolipin binding. Birk et al. (2013) reported that the SS-31⁠–⁠cardiolipin complex inhibited the peroxidase activity of cytochrome c, which oxidises cardiolipin. In a rat model of renal ischaemia, they measured cristae structure, mitochondrial swelling and ATP levels on reperfusion ².
• Electron transport. Szeto and Birk (2014) review the proposal that cardiolipin binding changes the efficiency of the electron transport chain, drawing on studies in several animal models ³.
• Clinical trials. In adults with primary mitochondrial myopathy, the MMPOWER trials used the six-minute walk test and symptom questionnaires as endpoints. The phase 1/2 trial enrolled 36 participants ⁴, the crossover MMPOWER-2 trial 30 ⁵, and the phase 3 MMPOWER-3 trial 218 ⁶. In MMPOWER-2, the difference in six-minute walk distance did not reach statistical significance ⁵. A post hoc analysis by the same group states that MMPOWER-3 did not show a significant difference from placebo in the overall genotypically diverse population ⁷.

Research areas

• Cell permeability and mitochondrial permeability transition (in vitro) ¹
• Cardiolipin binding and a rat renal ischaemia model (in vitro and animal) ²
• Electron transport chain efficiency (review) ³
• Randomised trials in primary mitochondrial myopathy (human) ^4,5,6
• Genotype-specific post hoc analysis of MMPOWER-3 (human) ⁷

Limits of the evidence

Most of the mechanistic literature comes from the group that developed the peptide, and the clinical trials were run by a single sponsor programme with overlapping investigators ^{1,2,3,4,5,6,7}.

The clinical trials studied a defined drug product in adults with genetically confirmed primary mitochondrial myopathy. Their findings describe that product in that population and setting, not research-grade material, and the larger trials did not meet their main endpoints in the overall population ^5,7.

Animal models differ in tissue, injury type and timing. Findings in one model should not be assumed to carry over to another.

OzPept’s SS-31 is a research chemical, not a medicine, and is not for human use.

Key studies

1. 2004In vitro

   Cell permeability and inner-membrane targeting ¹

2. 2013Animal

   Cardiolipin binding and rat renal ischaemia ²

3. 2018Human

   Phase 1/2 trial, 36 participants ⁴

4. 2020Human

   MMPOWER-2 crossover trial, 30 participants ⁵

5. 2023Human

   MMPOWER-3 phase 3 trial, 218 participants ⁶

6. 2024Human

   Post hoc genotype analysis of MMPOWER-3 ⁷

Questions

References

1. Zhao K, Zhao GM, Wu D, Soong Y, Birk AV, Schiller PW, et al. 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. Source
2. Birk AV, Liu S, Soong Y, Mills W, Singh P, Warren JD, 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. Source
3. Szeto HH, Birk AV. Serendipity and the discovery of novel compounds that restore mitochondrial plasticity. Clin Pharmacol Ther. 2014;96(6):672-683. Source
4. Karaa A, Haas R, Goldstein A, Vockley J, Weaver WD, Cohen BH. Randomized dose-escalation trial of elamipretide in adults with primary mitochondrial myopathy. Neurology. 2018;90(14):e1212-e1221. Source
5. Karaa A, Haas R, Goldstein A, Vockley J, Cohen BH. A randomized crossover trial of elamipretide in adults with primary mitochondrial myopathy. J Cachexia Sarcopenia Muscle. 2020;11(4):909-918. Source
6. Karaa A, Bertini E, Carelli V, Cohen BH, Enns GM, Falk MJ, 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. Source
7. Karaa A, Bertini E, Carelli V, Cohen B, Enns GM, Falk MJ, et al. Genotype-specific effects of elamipretide in patients with primary mitochondrial myopathy: a post hoc analysis of the MMPOWER-3 trial. Orphanet J Rare Dis. 2024;19(1):431. Source