Peptides as programmable molecular scaffolds: from chemical synthesis and engineering to translational medicine.

Peptides have evolved from naturally occurring ligands and classical hormones into a versatile and engineerable class of functional molecules. This review provides a comprehensive overview of the technological advances that collectively enable programmable peptide engineering across the entire discovery-to-development pipeline. We first discuss innovations in automated flow synthesis, chemoselective ligation, noncanonical residue incorporation, backbone editing, conformational constraint, and late-stage functionalization that have transformed peptide chemistry from linear sequence assembly into a modular engineering scaffold. We then examine modern discovery approaches, including phage display and mRNA display with the RaPID system, along with computational and AI-enabled design strategies that accelerate hit identification and multi-parameter optimization. Biophysical characterization techniques, cellular target engagement assays, and emerging delivery strategies are also reviewed as critical tools for bridging biochemical potency with intracellular activity. Finally, we discuss the translational barriers facing peptide therapeutics and the engineering strategies that have enabled successful clinical applications. Together, these advances establish a new era in which peptides are no longer viewed as inherently labile biomolecules but as chemically programmable scaffolds whose structures and functions can be precisely engineered.