Chemical Optimization of Temporin A–L Peptides: From Native Isoforms to Enhanced Antimicrobial Analogs

Temporins A–L, a family of short antimicrobial peptides isolated from the skin secretions of Rana temporaria , have emerged as promising scaffolds for the development of novel anti‐infective agents. However, their therapeutic translation is limited by issues such as modest selectivity, susceptibility to proteolytic degradation, and variable potency. In this review, we provide an overview of the medicinal chemistry efforts devoted to the optimization of this class of AMPs through systematic chemical modifications. Strategies including backbone alterations (e.g., D‐amino acid incorporation and retro‐inverso design), side chain modulation, charge tuning, hydrophobicity adjustment, and the introduction of noncanonical residues are discussed in relation to their impact on antimicrobial activity and selectivity. Particular attention is given to conformationally constrained analogs, such as cyclic, stapled, and bicyclic derivatives, which often display enhanced stability and bioactivity. By integrating available data, we delineated key structure–activity relationships governing temporin function and identified emerging design principles for the development of improved analogs. Finally, current challenges and future perspectives for the advancement of temporin‐based therapeutics in medicinal chemistry are outlined.