Plant Defense Peptides: Exploring the Structure-Function Correlation for Potential Applications in Drug Design and Therapeutics.

Defense peptides are part of plants' innate immune system and show widespread occurrence across the plant kingdom. Most of them belong to the category of antimicrobial peptides (AMPs) and act as strong chemical weapons against the biotic stresses that plants encounter. Plant AMP families exhibit remarkably conserved topology, being cysteine-rich with a conserved number of disulfide bridges stabilizing their three-dimensional structure, cationic in nature, and having hydrophobic surfaces. However, specific structural properties like amino acid sequence, distribution of charged and hydrophobic residues, secondary conformations, and polar angle play significant roles in fine-tuning their natural functions and their interactions with biological membranes. Considering their vital role in plant defense and strong structure-function relationships, these peptides have been explored for huge potential in human health and therapeutics. Owing to the structural flexibilities, cyclotides are considered promising scaffolds as drug design frameworks toward various targets and applications in therapeutics. To elaborate on this idea, we discuss the functional heterogeneity within the much-conserved cyclotide subfamilies. We discuss Möbius, bracelet, and trypsin inhibitor family cyclotides with respect to their membrane binding affinities pivoting on the surface charge and hydrophobicity. The decrease of peptide hydrophobicity and increase of electrostatic surface are associated with more specific antimicrobial selectivity and less toxicity to eukaryotic cells, widening their range of intracellular targets. We also discuss the application of AMPs in therapeutics and recent advances in the delivery of AMPs using nanosystems as vehicles.