Retro-Inverso Peptide

A retro-inverso peptide applies two changes at once to a parent: the residue order is reversed, and every residue is switched from L to D. Reversing the order flips each backbone amide, and inverting the chirality restores the side chains to roughly their original positions, so the analogue shows a similar side-chain surface on a mirror-image backbone that proteases do not recognise. In a one-letter string the whole sequence is lowercase and reads backwards relative to the parent.

The best-known example in the research market is FOXO4-DRI, the D-retro-inverso version of a FOXO4 segment that binds p53, carried into cells by a retro-inverso TAT tag. It was reported in 2017 to trigger apoptosis in senescent cells and to improve measures of frailty in aged and progeroid mice, and there has been no controlled human trial. No retro-inverso peptide has been approved as a drug.

What it settles is stability: hours or days of survival for a sequence that would otherwise last minutes, without adding a fatty acid or a polymer. What it does not settle is activity: side-chain mimicry is approximate and backbone hydrogen bonds point the wrong way, so a retro-inverso version can lose most of its affinity and must be tested as a new molecule. It works far more often where the parent binds as an extended strand than as a helix.

Three words get run together. A retro peptide is the reversed sequence in ordinary L-residues; an inverso peptide keeps the order and inverts every residue; only the combination is retro-inverso. All three have identical composition and mass, and so does the parent, so a matching mass spectrum cannot distinguish any of them; chiral analysis is the only check that addresses the property the analogue is sold on.