Hydrocarbon Stapled Antimicrobial Peptides

Abstract

Antimicrobial peptides are promising candidates for anti-infective pharmaceuticals. Unfortunately, because of their low proteolytic and chemical stability, their usage is generally narrowed down to topical formulations. Until now, numerous approaches to increase peptide stability have been proposed. One of them, peptide hydrocarbon stapling, a modification based on stabilizing peptide secondary structure with a side-chain covalent hydrocarbon bridge, have been successfully applied to many peptides. Moreover, constraining secondary structure of peptides have also been proven to increase their biological activity. This review article describes studies on hydrocarbon stapled antimicrobial peptides with respect to improved drug-like properties.

Towards Robust Delivery of Antimicrobial Peptides to Combat Bacterial Resistance

“…Cyclization of AMPs is a common method utilized to protect the peptide against protease degradation. This can be accomplished by utilizing disulphide bridges via cysteine residues akin to human defensins [161] or, more frequently, by incorporating one or more staples between i, i + 4 or i + 7 residues, which lock the peptide into an alpha-helical structure with twisted amide bonds that are less favourable to protease degradation [154,162]. A number of techniques have been developed to form these staples, including sulphur and nitrogen arylation of cysteine and lysine residues, respectively [163,164].…”

Design and structural characterisation of monomeric water-soluble α-helix and β-hairpin peptides: State-of-the-art

“…Diverse stapled peptides have been successfully designed offering promising therapeutic avenues [169,172,180]. For instance, lately reported antimicrobial and antiparasitic hydrocarbon-stapled peptides show optimal protease resistance and cellular penetrance [181][182][183][184]. Remarkably, two stapled peptides, a dual inhibitor of a protein/protein interaction and a growth hormone-releasing hormone inhibitor, have entered clinical trials [185].…”

Engineered Cationic Antimicrobial Peptides (eCAPs) to Combat Multidrug-Resistant Bacteria

“…Interestingly, the cysteine residues provide a bridge that does not substantially disrupt the helical structure (an important lesson), as shown by the helical wheel projection (Figure 4) and by the three-dimensional (3D) structure [119]. In this case, the disulfide bridge may have a similar effect to that of stapling the peptide [162,163], which may contribute to its activity. Thus, both SAAP-148 and ZY4 show some structural similarities to WLBU2 and could not have been obtained without some level of trial and error 13-14 years after the first study on WLBU2 was published.…”