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

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.

Deciphering C–H⋯O/X weak hydrogen bonding and halogen bonding interactions in aromatic peptoids

“…It is evident from Table 1 that the percentage of the trans population in 1-H is higher in CDCl 3 than in the rest of the solvents, corroborating with literature reports on acetylated proline-containing peptides. 62 In the DMSO- d 6 , CD 3 CN, and CD 3 OD polar solvents, 1-H has the highest trans configuration compared to halogen-substituted peptoids. The replacement of hydrogen with a halogen showed a significant decrease in the trans conformer population in polar solvents (Table 1).…”

Fluorinated Protein and Peptide Materials for Biomedical Applications

“…Another trait of protein and peptide materials that distinguish them from synthetic fluoropolymers is their intrinsic biological activities that make them prime candidates for adaptation as active pharmaceutical agents. Bioactive peptides are derived from food proteins and can be absorbed in the gastrointestinal system to employ several health benefits, such as preventing diseases or modulating physiological systems [ 74 ]. There is a broad range of functions, depending on the sequence of the bioactive peptides, with most mature research concerning the immune system.…”

“…They remain inactive while their sequences are kept within the parent protein, which also determines their structure, allowing them to be either linear α-helical peptides or β-sheet peptides. They are activated once released by hydrolysis during food processing and/or during gastrointestinal digestion [ 74 ]. When developing fluorinated bioactive peptides with antimicrobial and antiviral functions, it is important to limit fluorine mutations and manage the dosing schedule of the therapeutic to ensure that the toxicity does not become too great and that only the specific microbes intended to be killed are targeted.…”

“…When developing fluorinated bioactive peptides with antimicrobial and antiviral functions, it is important to limit fluorine mutations and manage the dosing schedule of the therapeutic to ensure that the toxicity does not become too great and that only the specific microbes intended to be killed are targeted. With respect to antimicrobial peptides specifically, studies have shown that the influence of increased hydrophobicity from limited fluorination at single positions can significantly improve proteolytic resistance as well as antimicrobial activity against both Gram-(+) and Gram-(−) bacteria without increasing toxic effects to mammalian cells [ 74 ].…”

Halogenated Pyrrolopyrimidines with Low MIC on Staphylococcus aureus and Synergistic Effects with an Antimicrobial Peptide

“…However, heavier halogen-containing antibiotics have been described from many different origins such as natural products [ 28 , 29 ], by microbial cultivation with halogen salts, [ 30 ], and synthetic origin [ 31 , 32 , 33 , 34 ]. Brominated tryptophanes and tyrosines are also frequently used in peptides with antibiotic effects [ 35 ]. Increased activity and stability of heavy halogen-modified peptide antibiotics has also been reported [ 36 ].…”