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.