Natural and Synthetic Halogenated Amino Acids-Structural and Bioactive Features in Antimicrobial Peptides and Peptidomimetics.

Mario Mardirossian,Michele Saviano,Mauro F A Adamo,Alessandro Tossi,Renato Gennaro,Marco Scocchi,Marina Rubini,Andrea Caporale

doi:10.3390/molecules26237401

Abstract

The 3D structure and surface characteristics of proteins and peptides are crucial for interactions with receptors or ligands and can be modified to some extent to modulate their biological roles and pharmacological activities. The introduction of halogen atoms on the side-chains of amino acids is a powerful tool for effecting this type of tuning, influencing both the physico-chemical and structural properties of the modified polypeptides, helping to first dissect and then rationally modify features that affect their mode of action. This review provides examples of the influence of different types of halogenation in amino acids that replace native residues in proteins and peptides. Examples of synthetic strategies for obtaining halogenated amino acids are also provided, focusing on some representative compounds and their biological effects. The role of halogenation in native and designed antimicrobial peptides (AMPs) and their mimetics is then discussed. These are in the spotlight for the development of new antimicrobial drugs to counter the rise of antibiotic-resistant pathogens. AMPs represent an interesting model to study the role that natural halogenation has on their mode of action and also to understand how artificially halogenated residues can be used to rationally modify and optimize AMPs for pharmaceutical purposes.

Highlights

We showed that halogenation can affect the structure, and in particular the conformations that can be adopted by peptides as well as protein folding
Fluorine is efficaciously used as an internal probe for F19-NMR studies of peptide and protein structure-activity relationships (SAR), especially in interaction with biological membranes [18,222]
SAR studies have revealed a correlation between the enhanced hydrophobicity resulting from halogenation and the antimicrobial activity of antimicrobial peptides (AMPs) and their pep-tidomimetics

Summary

Introduction

On one hand, the conformations of the backbone (α-helix, β-sheet, β-turn etc.) are the main determinants for three-dimensional structures, on the other, the arrangement of side chains in three-dimensional χ space Are the torsional angles of the side chain bonds) are determinant for molecular recognition, signal transduction, enzymatic specificity, immunomodulation, and other biological effects (Figure 1A). Using computational and experimental methods, it is possible to examine the effects of specific structural modifications in constraining the side chain groups of amino acid residues, or of their mimetics, in χ space [1]. The present work reviews the structural features induced by the presence of halogens on residue side-chains and the role of the halogen itself as well as of the synthesis and application of halogenated amino acids. The properties of halogenated antimicrobial peptides (AMPs), both native and synthetic, and their possible contribution to the growing problem of antibiotic resistance are considered

The Structural and Physico-Chemical Effects of Halogen Atoms in Polypeptides

Halo-Amino Acids and Halogenated Non-Ribosomal Peptides

Halogenated Tyrosines and Histidines

Halogenated Amino Acids in Non-Ribosomal Peptides

Halogenated Amino Acids in Water and Washed Food Products in the Environment

Synthesis of Naturally Occurring and Artificial Halogenated Amino Acids

Ribosomally-Synthesized Halogenated AMPs

Synthetic Halogenated AMPs

Future Perspectives and Conclusions