Beyond Simple Mimicry: Next-Generation Geometric Architectures and Future Paradigms in Small-Molecule and Macrocyclic Peptidomimetics.

Peptidomimetics have matured from motif‑based inhibitors into a structural engineering discipline that systematically translates peptide recognition surfaces into drug‑like scaffolds. Driven by the urgent clinical demand to overcome the inherent pharmacological liabilities of biomolecules, the field is undergoing a decisive Peptide-to-Small Molecule paradigm shift-functionally converting peptide-derived recognition motifs into orally bioavailable synthetic therapeutics. This Perspective highlights how foundational geometric design principles-linear repetition, convergent fusion, and cyclization-define next‑generation architectures capable of targeting complex protein-protein interactions (PPIs). Repeating‑unit oligomers exemplify linear projection strategies, heterocycle‑centered scaffolds embody the convergent fusion of recognition motifs, and macrocyclic frameworks pre-organize bioactive conformations while enabling access to non‑canonical topologies. Beyond simple mimicry, these architectures increasingly embrace dynamic responsiveness, aggregation remodeling, and universal multi‑structure platforms. We argue that the convergence of geometric logic with automated synthesis and AI‑driven design will transform peptidomimetics into a primary modality for decoding and therapeutically engaging the human interactome, including historically "undruggable" PPIs.