Structural Analysis of Amphibian, Insect, and Plant Host Defense Peptides Inspires the Design of Novel Therapeutic Molecules

Abstract

Host defense antimicrobial peptides (AMPs) are the key components of innate immune systems of both invertebrates and vertebrates. They play an important role in preventing microbial invasion and regulating immune response. This chapter intends to identify nature’s peptide design strategies based on a structural analysis of select AMPs from amphibians, insects, and plants. The plant kingdom and amphibian/insect classes have 250–1000 peptide entries in the antimicrobial peptide database. Both insects and plants deploy AMPs with a variety of structural scaffolds (α-helix, β-sheet, αβ-structure, and non-αβ structure). In contrast, amphibians make numerous defense peptides (combinatory libraries) based almost solely on the classic amphipathic α-helix structure. Thus, these 3-D structures suggest two general strategies for peptide discovery: (1) screening a library of peptides with a fixed backbone structure and (2) rational design by selecting a structural scaffold with a known target (e.g., cell walls, membranes, ribosomes, or nucleic acids). It is demonstrated that peptide library screening can be combined with structure-based design to better achieve the molecular design goals.