Peptide Drug Discovery through Secondary Structure Control

Peptides have long occupied an intermediate position between small molecules and macromolecular therapeutics in drug discovery, yet their practical application has been limited by intrinsic conformational flexibility and insufficient drug-like properties. Recent advances in the deliberate control of peptide secondary structure have fundamentally altered this perception, enabling peptides to function as designable molecular platforms. In particular, rational modulation of α-helical conformations has expanded the functional scope of peptides to include protein-protein interaction (PPI) inhibition, membrane-active antimicrobial functions, and intracellular drug delivery. This review summarizes our research on peptide drug discovery guided by secondary structure control as a unifying design principle. By emphasizing spatial organization within α-helical frameworks rather than primary sequence alone, we demonstrate how molecular recognition, membrane interaction, and cellular uptake can be systematically regulated. These concepts are demonstrated through the development of α-helix-based protein-protein interaction inhibitory peptides, amphipathic antimicrobial peptides with reduced cytotoxicity, and cell-penetrating peptides optimized for nucleic acid delivery. Furthermore, the extension of stabilized helical peptides to targeted protein degradation highlights their potential beyond conventional inhibition. In addition, we have worked to translate these research outcomes into societal implementation, with particular emphasis on regulatory development for peptide therapeutics. As part of these efforts, we contributed to the establishment and finalization of guidelines for the quality assessment and nonclinical safety evaluation of mid-sized peptide drugs. Collectively, these studies establish secondary structure control as a foundational concept for next-generation peptide therapeutics and their translation into clinically and socially viable modalities.