Also known as: Elamipretide · MTP-131 · Bendavia
SS-31 (Elamipretide) is a mitochondria-targeted tetrapeptide developed by Hazel Szeto and Peter Schiller at Weill Cornell Medicine. It selectively concentrates in the inner mitochondrial membrane by interacting with cardiolipin, protecting mitochondrial cristae architecture and ATP production — with demonstrated cardioprotection in ischemia-reperfusion injury.
Elamipretide belongs to the Szeto-Schiller (SS) peptide family, characterized by an alternating aromatic-cationic motif that drives rapid uptake into mitochondria without requiring a membrane potential gradient. This allows delivery to both healthy and dysfunctional mitochondria — a key advantage over older mitochondria-targeted compounds like MitoQ.
In a Phase 2 trial (PROGRESS-HF), elamipretide produced significant improvements in left ventricular end-systolic volume, a primary marker of cardiac remodeling, in heart failure with reduced ejection fraction (HFrEF) patients. The MITO-HF and PROGRESS trials also showed improvements in 6-minute walk distance and quality of life. A Phase 3 program (EMPOWER) is ongoing.
SS-31 binds with high affinity to cardiolipin — a phospholipid unique to the inner mitochondrial membrane that is essential for organizing cristae architecture and anchoring the respiratory chain supercomplexes (Complexes I–IV). In aging and disease, cardiolipin is oxidized by released cytochrome c, disrupting cristae and impairing ATP synthesis. SS-31 protects cardiolipin from oxidation and restores supercomplex organization.
By stabilizing respiratory chain supercomplexes, SS-31 reduces electron leak and mitochondrial ROS production at Complexes I and III. This reduces oxidative damage to mtDNA, proteins, and lipids — breaking the cycle of mitochondrial dysfunction that drives progressive cardiomyopathy.
SS-31 concentrates 1000-fold at the inner mitochondrial membrane via cardiolipin binding — no membrane potential gradient required (unlike MitoQ). Injection site reactions (erythema, swelling) are the most common adverse effect in clinical trials. Well-tolerated systemically with no significant cardiac, hepatic, or renal toxicity signals in Phase 2/3 trials. Store lyophilized powder at -20°C; reconstituted solution at 4°C for up to 7 days.
Phase 3 SPARCLE used a 5-day intensive SC infusion protocol. Research peptide protocols typically use 4–8 week subcutaneous injection cycles. No receptor downregulation or tachyphylaxis has been observed — the cardiolipin-binding mechanism is structural rather than receptor-mediated. Off-cycle monitoring of exercise capacity (6MWT) and quality of life markers is recommended.
Research compound only outside FDA Breakthrough Therapy program for Barth syndrome. Off-label human use requires research context. Long-term safety beyond 6 months is not established in published human data.
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