β‑Hairpin Antimicrobial Peptides: Class Diversity and Sequence Analysis

Interest in antimicrobial peptides has increased dramatically over the last few decades as researchers continue to explore their potential as alternatives to small molecules, as well as their applications in agriculture and food preservation. One promising yet small antimicrobial peptide class is that consisting of a single β-hairpin cyclized via intramolecular disulfide bonds, commonly termed β-hairpin antimicrobial peptides (β-AMPs). Their short length constrained cyclic structure and wide range of activities make them exciting to the general scientific community and drug developers alike; however, despite being found across several phyla, there remain fewer than 30 identified sequence families, making them exceedingly rare relative to more common structural classes. In this review, we identify and describe 27 unique macrocyclic β-AMP sequence families from the literature, with an emphasis on newer and lesser-known families. We then analyze the class’s sequence composition both as a whole and broken down by structural region, finding common characteristics including lengths of 11–25 amino acids, cationic charge, two or more cysteine pairs separated by at least three residues, and strong enrichment for arginine relative to lysine. We then discuss strategies for using these sequence characteristics to help expand the class and improve their relative underrepresentation.