A Chirality‐Guided Molecular Recognition Strategy for Targeting Intrinsically Disordered Proteins

Some peptide sequences are known to interact with their enantiomers to form stereocomplexes. However, the sequence-dependent conditions required for stereocomplexation have not been thoroughly elucidated. Here, we present a systematic investigation of peptide stereocomplexation using short tripeptides and their enantiomers. Stereocomplexation was evaluated by aggregate formation in mixed aqueous solutions, and single-crystal X-ray diffraction revealed racemic crystals. Stereocomplexation was driven by hydrophobic interactions between phenylalanine residues and electrostatic interactions involving lysine and the C-terminus. Thermodynamic and structural features of the complexation were further elucidated by calorimetry, simulations, and fluorescence assays. On the basis of these insights, a D-peptide (Ac-fffakr5-NH₂) was rationally designed to target the -FFAE- motif of amyloid β42 (Aβ42), a pathological intrinsically disordered protein. This D-peptide inhibited the fibrillization and cytotoxicity of Aβ42 in neuronal-like cells, outperforming a clinical candidate, peptide drug RD2. These findings establish peptide stereocomplexation as a viable strategy for constructing sequence-targeting ligands even against intrinsically disordered proteins.