SS-31 (Elamipretide)

SS-31 (D-Arg-2',6'-dimethyltyrosine-Lys-Phe-NH2) is a synthetic tetrapeptide developed by Hazel Szeto and Peter Schiller — hence Szeto-Schiller peptide #31 — at Weill Cornell Medical College. It belongs to the aromatic-cationic peptide class and is notable for a unique pharmacological property: it selectively accumulates at the inner mitochondrial membrane (IMM) without requiring an intact mitochondrial membrane potential for uptake, unlike conventional mitochondria-targeted compounds such as MitoQ. The cardiolipin-binding mechanism that concentrates SS-31 at the IMM is the most thoroughly characterized aspect of its pharmacology and has been confirmed by multiple independent research groups. Cardiolipin is an anionic phospholipid found almost exclusively at the IMM and plays a central structural role in organizing the electron transport chain (ETC) supercomplexes and cristae architecture. By stabilizing cardiolipin and preventing its peroxidation, SS-31 is proposed to preserve ETC efficiency, reduce mitochondrial reactive oxygen species (mtROS), improve ATP synthesis, and protect against mitochondrial permeability transition pore (mPTP) opening. SS-31 reached Phase II clinical trials under the name elamipretide (or MTP-131/Bendavia), with development led by Stealth BioTherapeutics. Two key Phase II trials — PROGRESS-HF (heart failure with reduced ejection fraction) and EMBRACE-STEMI (ST-elevation myocardial infarction, ischemia-reperfusion injury) — were conducted in the 2010s. Both failed to achieve their primary endpoints, though SS-31 demonstrated acceptable tolerability. Larger Phase III programs were discontinued. SS-31 is not FDA-approved. It appears in research peptide markets primarily due to community interest in mitochondrial optimization and longevity. This entry is for research and educational reference only.