SS-31

SS-31, also known as elamipretide, is a four-residue peptide with an alternating aromatic-cationic motif that concentrates at the inner mitochondrial membrane. Residue 2 is 2,6-dimethyltyrosine, modelled with both ring methyls in the PepXtide structural library, and the C-terminus is an amide rather than a free acid.

The compound belongs to the Szeto-Schiller series, first described in the Journal of Biological Chemistry in 2004 as cell-permeable peptides targeted to the inner mitochondrial membrane and built on alternating aromatic and basic residues. Its sequence is D-arginine, 2',6'-dimethyltyrosine, lysine and phenylalanine, carried as the C-terminal amide.

Every one of those four choices is doing work. The D-configured arginine and the C-terminal amide both remove ordinary peptidase recognition points. The amide also preserves the net charge at plus three by removing the C-terminal carboxylate that would otherwise offset one positive charge, and that net charge is the feature the alternating aromatic-cationic design depends on. The dimethylated tyrosine is a non-proteinogenic residue; analogues of the series lacking it were reported inactive in the original work.

The mechanism is the best evidenced in this part of the catalogue. The peptide binds cardiolipin, the signature phospholipid of the inner mitochondrial membrane, at roughly one-to-one stoichiometry with cardiolipin-containing model membranes, and inhibits the peroxidase activity that the cytochrome c and cardiolipin complex acquires. Reported observations in isolated mitochondria include higher cytochrome c reduction, retained cristae morphology and lower mitochondrial reactive oxygen species signal at nanomolar concentrations. The compound is reported to concentrate roughly a thousand-fold in the inner mitochondrial membrane relative to the surrounding medium.

Two refinements published since deserve to be stated alongside that account rather than omitted. Biophysical work shows the peptide partitions into the membrane interface with an affinity proportional to surface charge, so the interaction is not strictly cardiolipin-exclusive; and chemical cross-linking mass spectrometry on isolated mitochondria found contacts with numerous cardiolipin-binding oxidative-phosphorylation proteins, leading its authors to describe cardiolipin binding as necessary but not sufficient. The older framing of the compound as a free-radical scavenger rests mainly on the early work with the dimethylated tyrosine and is the weaker of the two accounts.

Laboratory characterisation uses solution NMR, isothermal titration calorimetry, membrane-potential and interface-sensitive fluorescent probes, and molecular dynamics, alongside isolated-mitochondria preparations for permeability-transition and swelling measurements. One specification point: the free base and the trihydrochloride salt differ substantially in formula mass, and the clinical-grade material is the trihydrochloride, which is freely soluble in water. The figure published on this page is the free-base mass, so a certificate stating a salt will not match it unless the basis is converted.