FOXO4-DRI vs SS-31 (Elamipretide)

FOXO4-DRI

FOXO4-DRI is a 46-residue D-retro-inverso peptide designed to interfere with the interaction between the FOXO4 protein and p53. It was reported in 2017 by Baar and colleagues, who took part of the FOXO4 p53-interaction domain, joined it to a cell-penetrating sequence and built the whole peptide from D-amino acids. All published work is preclinical: cultured human cells, mouse models of ageing and of lung fibrosis, and one rodent study in which clearing senescent cells made pulmonary haemodynamics worse. No human study was identified.

SS-31 (Elamipretide)

SS-31, also named elamipretide, is a synthetic tetrapeptide of alternating aromatic and basic residues that concentrates in mitochondria. Its sequence is D-Arg-Dmt-Lys-Phe-NH2, where Dmt is 2′,6′-dimethyltyrosine; the N-terminal D-amino acid slows enzymatic breakdown, and the peptide carries a net charge of +3 at neutral pH. The SS prefix refers to Szeto and Schiller, who described a series of related peptides that grew out of opioid peptide research, although SS-31 is reported to have no opioid activity. Most mechanistic work uses isolated mitochondria, cultured cells and rodent ischaemia models. It has also been tested in human clinical trials, chiefly in inherited mitochondrial disorders, and those data are smaller and less consistent than the preclinical literature.

How FOXO4-DRI acts

Baar and colleagues reported in 2017 that FOXO4 holds p53 in the nucleus of senescent cells, and that a peptide competing for that interaction causes p53 to leave the nucleus, followed by apoptosis in senescent cells selectively. Solution NMR work published in 2025 placed the binding site on the disordered transactivation domain of p53 and found that both the FOXO4-derived region and the cationic carrier sequence contribute. Selectivity for senescent cells is reported by several groups, in cell and rodent models only.

How SS-31 (Elamipretide) acts

SS-31 crosses cell membranes despite its positive charge and has been reported to accumulate at the inner mitochondrial membrane. The favoured explanation is binding to cardiolipin, a phospholipid largely confined to that membrane, through electrostatic and hydrophobic contacts. Biophysical studies suggest this binding changes membrane surface charge and the way cytochrome c associates with cardiolipin, including cytochrome c's peroxidase activity. In isolated mitochondria and cell models, its effects on cristae structure, electron transport and reactive oxygen species have been examined. Early papers described it as a direct antioxidant via its dimethyltyrosine; later work puts more weight on cardiolipin.

The records side by side

• Type: FOXO4-DRI, D-retro-inverso peptide; SS-31 (Elamipretide), Aromatic-cationic tetrapeptide — mitochondria-targeted
• Length: FOXO4-DRI, 46 amino acids; SS-31 (Elamipretide), 4 amino acids
• Molecular weight: FOXO4-DRI, 5358 g/mol; SS-31 (Elamipretide), 639.8 g/mol
• Molecular formula: FOXO4-DRI, C228H388N86O64; SS-31 (Elamipretide), C32H49N9O5

Reading a comparison

A comparison places two records side by side; it does not merge them. Each description above is drawn from that compound's own record, and the two were not necessarily characterised by the same methods, at the same time, or to the same level of detail. Before comparing any attribute, it is worth establishing that both records describe the substance you think they describe — names are not identifiers, and two entries sharing a name can differ in salt form, stereochemistry or the convention used to state a mass. Where a figure carries no method beside it, the comparison is between two reported numbers rather than between two measurements.