Structure–Activity Relationships and Rational Engineering of Plant Defense and Toxic Peptides

ABSTRACT

Plant‐derived peptides represent a rich source of structurally diverse and biologically potent scaffolds, characterized by high stability and a wide range of mechanisms of action. This review examines the structure–activity relationships (SAR) of these peptides, focusing on how key structural features—including disulfide connectivity, loop architecture, charge distribution, and backbone cyclization—govern their biological activity, selectivity, and toxicity. Representative peptide families such as cyclotides, defensins, thionins, and snakins are discussed to highlight conserved structural motifs alongside variable regions that contribute to functional diversity. We further explore rational design and engineering strategies, including loop grafting, cyclization, charge modulation, and backbone stabilization, supported by selected case studies demonstrating improved pharmacological profiles, membrane interactions, and target specificity. Building on these insights, we propose a design‐oriented framework that integrates SAR‐guided peptide engineering with experimental toxicology and pharmacological evaluation to facilitate the development of plant‐derived peptides as therapeutic leads and molecular tools. This peptide‐centric perspective aims to complement existing studies on plant bioactive peptides and to advance the rational design of next‐generation peptide‐based therapeutics.