Peptoids that mimic the structure, function, and mechanism of helical antimicrobial peptides

Abstract

Antimicrobial peptides (AMPs) and their mimics are emerging as promising antibiotic agents. We present a library of ''ampetoids'' (antimicrobial peptoid oligomers) with helical structures and biomimetic sequences, several members of which have low-micromolar antimicrobial activities, similar to cationic AMPs like pexiganan. Broad-spectrum activity against six clinically relevant BSL2 pathogens is also shown. This comprehensive structure-activity relationship study, including circular dichroism spectroscopy, minimum inhibitory concentration assays, hemolysis and mammalian cell toxicity studies, and specular x-ray reflectivity measurements shows that the in vitro activities of ampetoids are strikingly similar to those of AMPs themselves, suggesting a strong mechanistic analogy. The ampetoids' antibacterial activity, coupled with their low cytotoxicity against mammalian cells, make them a promising class of antimicrobials for biomedical applications. Peptoids are biostable, with a protease-resistant N-substituted glycine backbone, and their sequences are highly tunable, because an extensive diversity of side chains can be incorporated via facile solid-phase synthesis. Our findings add to the growing evidence that nonnatural foldamers will emerge as an important class of therapeutics.antibiotics ͉ peptidomimetics ͉ structure-activity studies N atural antimicrobial peptides (AMPs) defend a wide array of organisms against bacterial pathogens and show potential as supplements for or replacements of conventional antibiotics, because few bacteria have evolved resistance to them (1-3). Many AMPs kill bacteria by permeabilization of the cytoplasmic membrane, causing depolarization, leakage, and death (4), whereas others target additional anionic bacterial constituents (e.g., DNA, RNA, or cell wall components) (2, 5). Amphipathic secondary structures in which residues are segregated into hydrophobic and cationic regions ( Fig. 1 A and B) are the hallmark of most AMPs (6). Regardless of their final target of killing, AMPs must interact with the bacterial cytoplasmic membrane, and their amphipathicity is integral to such interactions (1, 2, 7). Additionally, their cationic nature imparts AMPs with some measure of selectivity, because mammalian cell membranes are largely zwitterionic. The precise nature of AMP-membrane interactions remains controversial and actively debated; a variety of mechanisms have been proposed, including the carpet (4), barrel-stave pore (4), toroidal pore (8), and aggregate (9) models. Nevertheless, a considerable number of structure-activity investigations have elucidated how the physicochemical properties of these molecules relate to their biological activities (4,7,(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22).Although AMPs have been actively studied for decades (23-25), they have yet to see widespread clinical use (1). This is due in part to the vulnerability of many peptide therapeutics to rapid in vivo degradation, which dramatically reduces their bioavailability. Nonnatural mimics of AMPs...

Potential pharmacological chaperones targeting cancer-associated MCL-1 and Parkinson disease-associated α-synuclein

“…Because α-helix-mediated PPIs are involved in various cellular signaling pathways, there have been tremendous efforts to develop molecules that can mimic helical peptide structures to modulate such interactions (18,22). These include stabilized helical peptides (15)(16)(17)23) and peptidomimetic foldamers (24)(25)(26)(27)(28)(29). Alternatively, nonpeptidic, small-molecule α-helix mimetics have attracted significant interest.…”

Antimicrobial cationic polymers: from structural design to functional control

“…Inspired by α-helical conformation of AMPs, many research works have focused on improving the α-helical β-peptides and peptoids for antimicrobials. [58][59][60][61] As shown in Figure 4, Gellman and co-workers reported an artificial α-helical β-peptides displaying antimicrobial activity against E. coli, Bacillus subtilis, Enterococcus faecium and S. aureus, which is similar to the natural peptide (magainin). 62 The MICs to these four kinds of bacteria were 6.3, 1.6, 12.5 and 3.2 μg ml − 1 , respectively, by incubating the bacteria for 6 h at 37°C.…”

Surface-immobilised antimicrobial peptoids

“…For example, the linear cationic α-helical class of AMPs have been successfully mimicked as β-peptides and as poly-N-substituted glycines (peptoids) (Porter et al, 2002;Chongsiriwatana et al, 2008). Peptoids are non-natural mimics of polypeptides with the side chains appended to the amide nitrogen instead of the α-carbon (Zuckermann et al, 1992).…”