Post-Translational Modifications of Natural Antimicrobial Peptides and Strategies for Peptide Engineering

Abstract

Natural antimicrobial peptides (AMPs) are gene-coded defense molecules discovered in all the three life domains: Eubacteria, Archaea, and Eukarya. The latter covers protists, fungi, plants, and animals. It is now recognized that amino acid composition, peptide sequence, and posttranslational modifications determine to a large extent the structure and function of AMPs. This article systematically describes post-translational modifications of natural AMPs annotated in the antimicrobial peptide database (http://aps.unmc.edu/AP). Currently, 1147 out of 1755 AMPs in the database are modified and classified into more than 17 types. Through chemical modifications, the peptides fold into a variety of structural scaffolds that target bacterial surfaces or molecules within cells. Chemical modifications also confer desired functions to a particular peptide. Meanwhile, these modifications modulate other peptide properties such as stability. Elucidation of the relationship between AMP property and chemical modification inspires peptide engineering. Depending on the objective of our design, peptides may be modified in various ways so that the desired features can be enhanced whereas unwanted properties can be minimized. Therefore, peptide design plays an essential role in developing natural AMPs into a new generation of therapeutic molecules.

The role of C-terminal amidation in the membrane interactions of the anionic antimicrobial peptide, maximin H5

“…In general, this activity involves membrane interaction [3,4] and increasingly, it has been found that post-translational modifications (PTMs) play a role in optimising the efficacy and specificity of these mechanisms of action [5][6][7][8][9]. Most of the PTMs identified in AMPs are relatively infrequent in occurrence [6], typically the phosphorylation of residues [1,6,10] and the chiral inversion of residues to produce D-amino acids [11][12][13]. However, two PTMs have been found to be ubiquitous amongst AMPs of eukaryotes [6] of which the first is the oxidation of cysteine residues to form disulphide bridges [14].…”

“…Most of the PTMs identified in AMPs are relatively infrequent in occurrence [6], typically the phosphorylation of residues [1,6,10] and the chiral inversion of residues to produce D-amino acids [11][12][13]. However, two PTMs have been found to be ubiquitous amongst AMPs of eukaryotes [6] of which the first is the oxidation of cysteine residues to form disulphide bridges [14]. It is generally accepted that disulphide bridges play a major architectural role in the antimicrobial action of AMPs [6], primarily by maintaining the amphiphilic topography of the molecules and thereby their ability to interact with target membranes and kill host cells [5,15].…”

“…However, two PTMs have been found to be ubiquitous amongst AMPs of eukaryotes [6] of which the first is the oxidation of cysteine residues to form disulphide bridges [14]. It is generally accepted that disulphide bridges play a major architectural role in the antimicrobial action of AMPs [6], primarily by maintaining the amphiphilic topography of the molecules and thereby their ability to interact with target membranes and kill host cells [5,15]. This form of structural stabilisation is also important for the therapeutic development of AMPs as seen with the cysteine knot architectures of cyclotides from plants [2,16].…”

“…The second most common PTM found in AMPs is the introduction of C-terminal moieties, which have predominantly been identified in amphibians [6]. These fall into two major classes: the presence of either a Rana box [20] or an amide group [21].…”

Natural Antifungal Peptides/Proteins as Model for Novel Food Preservatives

“…These two characteristics have been identified in several AFPs (Mura et al, 2016). Amidation of a peptide at its C-terminus has become of increasing interest, due to the removal of the negative charge, increasing antifungal activity and supporting resistance against proteases (Torrent, Andreu, Nogués, & Boix, 2011;Wang, 2014). Thus, the anti-Candida activity of P-113, a 12-amino acid fragment of Hst, is increased after amidation (Rothstein et al, 2001).…”