Design Rationale for a Retroinverso 4-Fluorophenylalanine SS-31 Analogue (RI-4FPhe-SS31)

This document describes the design rationale, predicted properties, and molecular

specification for RI-4FPhe-SS31, a retroinverso analogue of the mitochondria-targeted

tetrapeptide SS-31 (elamipretide, D-Arg-Dmt-Lys-Phe-NH2) incorporating a

4-fluorophenylalanine substitution. The two modifications address independent metabolic

vulnerabilities of the parent compound: the retroinverso backbone confers resistance to

endogenous peptidases, while the 4-fluorine substitution on the C-terminal phenylalanine

blocks CYP450-mediated aromatic hydroxylation. The combined effect is predicted to extend

the plasma half-life of the molecule while preserving the net +3 charge and the spatial

arrangement of cationic and aromatic side chains required for selective interaction with

cardiolipin at the inner mitochondrial membrane. This document is published as prior art under

CC-BY 4.0 to ensure permanent public domain availability.