Design of Oligourea-Based Foldamers with Antibacterial and Antifungal Activities

Abstract

There is an urgent need to develop new therapeutic strategies to fight the emergence of multidrug resistant bacteria. Many antimicrobial peptides (AMPs) have been identified and characterized, but clinical translation has been limited partly due to their structural instability and degradability in physiological environments. The use of unnatural backbones leading to foldamers can generate peptidomimetics with improved properties and conformational stability. We recently reported the successful design of urea-based eukaryotic cell-penetrating foldamers (CPFs). Since cell-penetrating peptides and AMPs generally share many common features, we prepared new sequences derived from CPFs by varying the distribution of histidine- and arginine-type residues at the surface of the oligourea helix, and evaluated their activity on both Gram-positive and Gram-negative bacteria as well as on fungi. In addition, we prepared and tested new amphiphilic block cofoldamers consisting of an oligourea and a peptide segment whereby polar and charged residues are located in the peptide segment and more hydrophobic residues in the oligourea segment. Several foldamer sequences were found to display potent antibacterial activities even in the presence of 50% serum. Importantly, we show that these urea-based foldamers also possess promising antifungal properties.

Unnatural helical peptidic foldamers as protein segment mimics

“…In recent years, more membrane-active helical unnatural foldamers have been developed as antimicrobial agents. [91][92][93][94][95][96][97][98][99][100][101][102][103] These latest works involve helical b-peptides, peptoids, g-peptides, sulfono-g-AApeptides, oligoureas, and so on. 95 They next designed a/b-peptide analogues with different a/b-amino acid organizations by replacing a-amino acid residues with b-amino acid residues to generate aab, aaab and aabaaab repeating units.…”

“…In recent years, more membrane-active helical unnatural foldamers have been developed as antimicrobial agents. 91–103 These latest works involve helical β-peptides, peptoids, γ-peptides, sulfono-γ-AApeptides, oligoureas, and so on.…”

“…18B , 53 ). 97 In addition, they also prepared and tested novel amphiphilic block cofolders consisting of oligourea and peptide stretches, in which polar and charged residues are located in the peptide stretches and more hydrophobic residues are located in the oligourea stretches. Some of them were found to show potent antibacterial activity even in the presence of 50% serum and also have promising antifungal properties.…”

Progress of polymer-based strategies in fungal disease management: Designed for different roles

“…Their antimicrobial activity is correlated with their unique pattern of chemical structure that can be imitated in material design. Numerous natural AMPs are recorded and annotated, and the development of synthetic AMPs never ends ( Wang et al., 2016 ; Ramamourthy et al., 2020 ; Tallet et al., 2022 ). Their antifungal mechanisms involve pore formation, mannan-binding, nucleic acid, and cell wall inhibition ( De Cesare et al., 2020 ).…”

C-Terminal-Modified Oligourea Foldamers as a Result of Terminal Methyl Ester Reactions under Alkaline Conditions

“…In recent years, oligourea foldamers with the general formula [NHCH(R)CH 2 NHCO] n have gained much attention as structural and functional mimetics of peptides [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. It has been shown that oligoureas can mimic the helical secondary structure of peptides.…”