SS-31, also known as Elamipretide, is a synthetic compound developed to address cellular energy failure by targeting mitochondria. These organelles function as the powerhouses of cells, generating the energy required for life processes. Mitochondrial dysfunction is recognized as a common factor underlying a wide range of degenerative and age-related diseases. Elamipretide is designed to penetrate cells and accumulate exclusively within the mitochondria to stabilize their internal machinery.
The Structure and Target of the SS-31 Peptide
Elamipretide is classified as a small, synthetic tetrapeptide. Its chemical design includes alternating aromatic and positively charged (cationic) residues. This cationic structure allows the peptide to selectively pass through cell membranes and enter the mitochondria. The negative electrical potential across the inner mitochondrial membrane attracts the positively charged Elamipretide, causing it to concentrate there thousands of times more than elsewhere in the cell.
Once inside, the peptide targets a unique phospholipid called cardiolipin, found almost exclusively in the inner mitochondrial membrane. Cardiolipin plays a structural role in organizing the protein complexes of the electron transport chain (ETC), the system responsible for generating cellular energy. By binding to this lipid, Elamipretide helps maintain the architecture and integrity of the inner membrane folds, known as cristae. This stabilization ensures the energy-producing machinery operates efficiently.
Mitigating Oxidative Stress and Boosting Cellular Energy
Mitochondrial dysfunction often begins when cardiolipin becomes damaged through peroxidation. This damage destabilizes the inner membrane, leading to an increase in the production of Reactive Oxygen Species (ROS) as the electron transport chain becomes disorganized. The membrane’s structural failure also causes the mitochondria to swell, further impairing function. Elamipretide directly addresses this problem by binding to the damaged cardiolipin and acting as a scaffold to normalize the membrane structure.
This binding action helps prevent further cardiolipin peroxidation. By stabilizing the inner membrane, Elamipretide restores the optimal organization of the electron transport chain complexes into functional “supercomplexes.” A properly organized chain facilitates the smooth transfer of electrons, which significantly reduces the leakage of electrons that creates ROS. The result of this stabilization is an improvement in the efficiency of oxidative phosphorylation, the process that generates adenosine triphosphate (ATP), the cell’s primary energy currency.
Specific Diseases Under Clinical Investigation
The therapeutic potential of Elamipretide is being explored across a diverse range of diseases where energy deficiency and oxidative damage are prominent features. One major focus is primary mitochondrial myopathy (PMM), a rare neuromuscular disorder characterized by debilitating muscle weakness and fatigue due to inherited mitochondrial defects. In PMM, the peptide aims to enhance ATP production in muscle cells to improve endurance and functional capacity.
Clinical investigation also includes dry age-related macular degeneration (dry AMD), a progressive eye disease where mitochondrial stress contributes to the death of retinal cells. By targeting mitochondria within the retina, Elamipretide seeks to protect these highly energetic cells from oxidative damage and slow vision loss. The peptide has also been studied in chronic kidney disease (CKD), particularly in cases involving ischemia-reperfusion injury, where rapid ATP recovery is crucial for preserving kidney function.
Another condition under scrutiny is Barth syndrome, a genetic disorder that specifically impairs cardiolipin metabolism, leading to severe heart and skeletal muscle problems. Since Elamipretide directly interacts with cardiolipin, it is a strong therapeutic candidate for this condition. In all these conditions, the fundamental strategy remains the same: to interrupt the cycle of mitochondrial damage and energy depletion that drives the disease pathology.
The Current Development Status of Elamipretide
Elamipretide has advanced into late-stage clinical development for several indications. It is currently being evaluated in Phase 3 trials for dry age-related macular degeneration and primary mitochondrial myopathy. These large-scale studies are designed to confirm the safety and effectiveness of the compound before it can be considered for regulatory approval.
Development for Barth syndrome has been active, receiving both Fast Track and Orphan Drug designations from the U.S. Food and Drug Administration (FDA). The company recently resubmitted a New Drug Application (NDA) for accelerated approval, following a previous FDA request. This resubmission is based on data showing improvements in knee extensor muscle strength, which the agency acknowledged as a potential intermediate clinical endpoint. While the drug is not yet commercially available, its status in Phase 3 indicates it remains a significant focus in mitochondrial medicine.