Unlocking the therapeutic potential of native peptides by non-symmetric stapling

Protein-protein interactions (PPIs) underlie most cellular processes and many diseases, yet remain largely undruggable by small molecules. Evolution has optimized short peptide segments (hotspot sequences) for precise recognition, but when isolated from their protein context, these segments often lose structure and bioactivity. Traditional strategies for restoring threedimensional structure and function require sequence reengineering, typically involving the introduction of non-natural amino acids or identical reactive residues. Recently emerged nonsymmetric stapling shifts this paradigm by crosslinking chemically differentiated natural residues, thereby restoring native-like topology and function while preserving the primary sequence. Combined with high-throughput display technologies and computational design, this strategy enables direct translation of native PPI segments into therapeutic leads. Such approaches may redefine peptide discovery by preserving, rather than redesigning, sequences optimized by nature.