Shaping the future of constrained peptides and compact proteins in drug discovery

Constrained peptides and compact proteins are potent alternatives to conventional drug modalities in academia and industry. Located in the chemical space between small molecules and classical biologics, these drug formats feature highly modular, conformationally constrained turns and loops that can be accessed through rational design, selection-based screening or computational discovery. The amino acid-derived biopolymers can engage comparatively featureless protein surfaces more effectively than low molecular weight compounds, yet at the same time offer greater potential to reach intracellular targets than larger biologics. This combination allows them to address medicinal chemistry challenges that conventional approaches struggle to solve. In this brief review, selected advances in the discovery and development of such structures are highlighted, especially those where screening of genetically encoded or synthetic libraries played a central role. Several recent examples of rational design and computationally generated peptide and protein scaffolds are also discussed, including those driven by machine learning and artificial intelligence. Across these strategies, all case studies describe the successful identification and refinement of cyclic peptides or compact proteins with antibody-like binding as promising lead structures. As the presented examples cover a wide range of structural topologies and medicinally relevant targets, they reflect the growing importance of cyclic peptides and compact proteins as new molecular modalities for drug discovery and development.