The α-helix, a fundamental and highly versatile secondary structure in proteins, holds substantial promise in biomedicine owing to its characteristic right-handed helical conformation, regular hydrogen-bonding network, and predictable side-chain arrangement. This review systematically outlines the structural features and stabilization mechanisms of α-helical peptides, along with core strategies in drug design, including solid-phase peptide synthesis (SPPS), ring-opening polymerization (ROP) of N-carboxyanhydrides (NCAs), conformational stapling, non-natural amino acid incorporation, and stimuli-responsive modifications. We also highlight frontier advances in computational simulation and deep-learning approaches for de novo structural prediction and functional optimization. Regarding applications, this review elaborates on the mechanisms and recent progress of α-helical peptides in antimicrobial and anticancer therapies, immunomodulation, and tissue engineering, covering membrane-targeting mechanisms, immune cell modulation, vaccine design, drug delivery systems, and bioactive regenerative scaffolds. Despite their superior biocompatibility, functional programmability, and translational potential of α-helical peptides, challenges remain including in vivo stability, scalable manufacturing, and optimizing pharmacokinetics. Future advances driven by multidisciplinary integration and artificial intelligence (AI)-guided design are expected to further enable α-helical peptides as pivotal tools in precision and regenerative medicine.
Yin et al. (Mon,) studied this question.