SS-31

Research · SS-31

Overview

SS-31 (elamipretide, D-Arg-Dmt-Lys-Phe-NH2) is a cell-permeable four-residue aromatic-cationic sequence developed by Szeto and Schiller. Alternating aromatic and basic residues, including 2',6'-dimethyltyrosine, allow it to pass through cell membranes independently of energy or transporters and concentrate several-fold at the inner mitochondrial membrane. Elamipretide has received regulatory approval in the United States. It is studied as a reference compound in mitochondrial bioenergetics research. Its development grew out of earlier opioid-ligand chemistry in which the Szeto-Schiller sequences were found to localize to mitochondria. It lacks meaningful opioid receptor activity and is classed instead as a mitochondria-targeted agent.

Mechanism of action

Binds selectively to cardiolipin, an anionic phospholipid unique to the inner mitochondrial membrane, through electrostatic and hydrophobic interactions. Cardiolipin binding stabilizes cristae architecture and the organization of electron transport chain supercomplexes. It also inhibits the peroxidase activity of the cytochrome c-cardiolipin complex, preserving cytochrome c's electron-carrier function and limiting cardiolipin oxidation. These effects are reported to improve coupling of electron transport to ATP synthesis, reduce reactive oxygen species generation, and limit mitochondrial permeability transition and cytochrome c release. Because its uptake does not depend on mitochondrial membrane potential, it reaches depolarized mitochondria that cationic dye-based targeting agents fail to enter.

Key research findings

1. 01

   In vitro assays demonstrate selective cardiolipin binding and inhibition of cytochrome c peroxidase activity in isolated mitochondria.

2. 02

   Rodent ischemia-reperfusion models of kidney and heart characterize preservation of mitochondrial cristae and ATP synthesis.

3. 03

   Aged rodent studies characterize effects on cardiac and skeletal muscle mitochondrial function and protein modifications.

4. 04

   Clinical trials in primary mitochondrial myopathy and Barth syndrome have characterized functional and exercise-capacity endpoints.

Published references

• The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin

  Birk AV et al. — J Am Soc Nephrol, 2013 · PMID: 23813215

• First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics

  Szeto HH — Br J Pharmacol, 2014 · PMID: 24117165

The information above is derived from published preclinical and clinical research. It is provided for educational purposes only and does not constitute medical advice, diagnosis, or treatment recommendations.