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Although antimicrobial peptides have been shown to inactivate viruses through disruption of their viral envelopes, clinical use of such peptides has been hampered by a number of factors, especially their enzymatically unstable structures. To overcome the shortcomings of antimicrobial peptides, peptoids (sequence-specific N-substituted glycine oligomers) mimicking antimicrobial peptides have been developed. We aimed to demonstrate the antiviral effects of antimicrobial peptoids against hepatitis B virus (HBV) in cell culture. The anti-HBV activity of antimicrobial peptoids was screened and evaluated in an infection system involving the HBV reporter virus and HepG2.2.15-derived HBV. By screening with the HBV reporter virus infection system, three (TM1, TM4, and TM19) of 12 peptoids were identified as reducing the infectivity of HBV, though they did not alter the production levels of HBs antigen in cell culture. These peptoids were not cytotoxic at the evaluated concentrations. Among these peptoids, TM19 was confirmed to reduce HBV infection most potently in a HepG2.2.15-derived HBV infection system that closely demonstrates authentic HBV infection. In cell culture, the most effective administration of TM19 was virus treatment at the infection step, but the reduction in HBV infectivity by pre-treatment or post-treatment of cells with TM19 was minimal. The disrupting effect of TM19 targeting infectious viral particles was clarified in iodixanol density gradient analysis. In conclusion, the peptoid TM19 was identified as a potent inhibitor of HBV. This peptoid prevents HBV infection by disrupting viral particles and is a candidate for a new class of anti-HBV reagents., Competing Interests: Declaration of competing interest A.E.B. is a shareholder and member of the Board of Directors of Maxwell Biosciences; N.M. is a consultant for Maxwell Biosciences., (Copyright © 2024 Elsevier B.V. All rights reserved.)

We have studied the complexation between cationic antimicrobials and polyanionic microgels to create self-defensive surfaces that responsively resist bacterial colonization. An essential property is the stable sequestration of the loaded (complexed) antimicrobial within the microgel under a physiological ionic strength. Here, we assess the complexation strength between poly(acrylic acid) [PAA] microgels and a series of cationic peptoids that display supramolecular structures ranging from an oligomeric monomer to a tetramer. We follow changes in loaded microgel diameter with increasing [Na + ] as a measure of the counterion doping level. Consistent with prior findings on colistin/PAA complexation, we find that a monomeric peptoid is fully released at ionic strengths well below physiological conditions, despite its +5 charge. In contrast, progressively higher degrees of peptoid supramolecular structure display progressively greater resistance to salting out, which we attribute to the greater entropic stability associated with the complexation of multimeric peptoid bundles.

Antimicrobial peptides (AMPs) are promising therapeutics in the fight against multidrug-resistant bacteria. As a mimic of AMPs, peptoids with N-substituted glycine backbone have been utilized for antimicrobials with resistance against proteolytic degradation. Antimicrobial peptoids are known to kill bacteria by membrane disruption; however, the nonspecific aggregation of intracellular contents is also suggested as an important bactericidal mechanism. Here,structure-activity relationship (SAR) of a library of indole side chain-containing peptoids resulting in peptoid 29 as a hit compound is investigated. Then, quantitative morphological analyses of live bacteria treated with AMPs and peptoid 29 in a label-free manner using optical diffraction tomography (ODT) are performed. It is unambiguously demonstrated that both membrane disruption and intracellular biomass flocculation are primary mechanisms of bacterial killing by monitoring real-time morphological changes of bacteria. These multitarget mechanisms and rapid action can be a merit for the discovery of a resistance-breaking novel antibiotic drug., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Cationic amphipathic structures are often utilized in natural membrane-active host-defense peptides. Negatively charged surface membranes of rapidly proliferating bacterial and cancer cells have been targeted by various synthetic peptides and peptidomimetics adopting the structural motif. Herein, we synthesized a set of conjugates composed of cationic amphipathic peptoids (i.e., oligo-N-substituted glycines) and a chlorin photosensitizer, named chlorin e6 (Ce6)-peptoid conjugates (CPCs). Among the nine CPCs, CPC 7, composed of Ce6, a PEG linker, and guanidine-rich helical amphipathic peptoids, exhibited a distinct photoresponsive inactivation of Gram-positive and Gram-negative bacteria. Subsequent studies showed that CPC 7 effectively killed various cancer cells after irradiation with red light (655 nm), suggesting the potential of CPC 7 as a dual antimicrobial and anticancer agent. Confocal laser scanning microscopy and flow cytometry data suggested that CPC 7 could induce apoptotic cell death. Our results show the potential of peptoid-based photosensitizer conjugates as a versatile platform for antimicrobial and anticancer photodynamic therapy agents and peptoid therapeutics., (© 2022. The Author(s), under exclusive licence to European Photochemistry Association, European Society for Photobiology.)

Peptide mimics, possessing excellent biocompatibility and protease stability, have attracted broad attention and research in the biomedical field. β-Peptides and β-peptoids, as two types of vital peptide mimics, have demonstrated great potential in the field of foldamers, antimicrobials and protein binding, etc. Currently, the main synthetic strategies for β-peptides and β-peptoids include solid-phase synthesis and polymerization. Among them, polymerization in one-pot can minimize the repeated separation and purification used in solid-phase synthesis, and has the advantages of high efficiency and low cost, and can synthesize β-peptides and β-peptoids with high molecular weight. This review summarizes the polymerization methods for β-peptides and β-peptoids. Moreover, future developments of the polymerization method for the synthesis of β-peptides and β-peptoids will be discussed., (© 2022 Wiley-VCH GmbH.)

Recent outbreaks of both new and existing infectious pathogens have threatened healthcare systems around the world. Therefore, it is vital to detect and neutralize pathogens to prevent their spread and treat infected patients. This consideration has led to the development of biosensors and antibiotics inspired by the structure and function of antibodies and antimicrobial peptides (AMPs), which constitute adaptive and innate immunity, efficiently protecting the human body against invading pathogens. Herein, we provide an overview of recent advances in the detection and neutralization of pathogens using protein-mimetic peptoid nanoarchitectures. Peptoids are bio-inspired and sequence-defined polymers composed of repeating N -substituted glycine units. They can spontaneously fold into well-defined three-dimensional nanostructures that encode chemical information depending on their sequences. Loop-functionalized peptoid nanosheets have been constructed by mimicking antibodies containing chemically variable loops as binding motifs for their respective target pathogen. Furthermore, by mimicking the cationic amphipathic features of natural AMPs, helical peptoids and their assemblies have been developed to achieve selective anti-infective activity owing to their intrinsic ability to interact with bacterial membranes and viral envelopes. We believe that this mini-review furnishes in-depth insight into how to construct protein-like nanostructures via the self-assembly of peptoids for application in the detection of pathogens and the treatment of infectious diseases for future healthcare applications.

Antimicrobial peptides (AMPs) are promising pharmaceutical candidates for the prevention and treatment of infections caused by multidrug-resistant ESKAPE pathogens, which are responsible for the majority of hospital-acquired infections. Clinical translation of AMPs has been limited, in part by apparent toxicity on systemic dosing and by instability arising from susceptibility to proteolysis. Peptoids (sequence-specific oligo- N -substituted glycines) resist proteolytic digestion and thus are of value as AMP mimics. Only a few natural AMPs such as LL-37 and polymyxin self-assemble in solution; whether antimicrobial peptoids mimic these properties has been unknown. Here, we examine the antibacterial efficacy and dynamic self-assembly in aqueous media of eight peptoid mimics of cationic AMPs designed to self-assemble and two nonassembling controls. These amphipathic peptoids self-assembled in different ways, as determined by small-angle X-ray scattering; some adopt helical bundles, while others form core-shell ellipsoidal or worm-like micelles. Interestingly, many of these peptoid assemblies show promising antibacterial, antibiofilm activity in vitro in media, under host-mimicking conditions and antiabscess activity in vivo. While self-assembly correlated overall with antibacterial efficacy, this correlation was imperfect. Certain self-assembled morphologies seem better-suited for antibacterial activity. In particular, a peptoid exhibiting a high fraction of long, worm-like micelles showed reduced antibacterial, antibiofilm, and antiabscess activity against ESKAPE pathogens compared with peptoids that form ellipsoidal or bundled assemblies. This is the first report of self-assembling peptoid antibacterials with activity against in vivo biofilm-like infections relevant to clinical medicine.

Background: Antimicrobial peptides (AMPs) are short, cationic, amphipathic molecules that have gained tremendous popularity as alternatives to traditional antibiotics due to their lower propensity to develop bacterial resistance. However, the clinical developability of AMPs remains impeded due to shortcomings such as proteolytic instability and poor penetration leading to low bioavailability., Aims: To improve the access of AMPs to cells and subsequent bacteria killing, we evaluated the cell-penetrating and antimicrobial properties of three novel libraries of synthetic peptoids using Minimum Inhibitory Concentration, killing efficacy and membrane permeabilization assays against mycobacteria and Staphylococcus aureus . In addition, we investigated cell selectivity using mammalian cells to assess peptoid toxicity., Results: We showed that short tetrameric Rhodamine B-labeled peptoids composed of a balance of aromatic and lipophilic residues have potent selective antimicrobial activity against a range of microorganisms. The most potent candidates were active against drug-resistant S. aureus isolates as well as mycobacterial strains, with cell penetrating capabilities reported in HeLa and RAW 264.7 macrophage cells., Conclusions: These data suggest that peptoids with novel dual functionalities may potentially be an interesting class of therapeutics and/or molecular delivery agents for anti-infective purposes., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s). Published by IMR Press.)

Many organisms rely on antimicrobial peptides (AMPs) as a first line of defense against pathogens. In general, most AMPs are thought to kill bacteria by binding to and disrupting cell membranes. However, certain AMPs instead appear to inhibit biomacromolecule synthesis, while causing less membrane damage. Despite an unclear understanding of mechanism(s), there is considerable interest in mimicking AMPs with stable, synthetic molecules. Antimicrobial N-substituted glycine (peptoid) oligomers ("ampetoids") are structural, functional and mechanistic analogs of helical, cationic AMPs, which offer broad-spectrum antibacterial activity and better therapeutic potential than peptides. Here, we show through quantitative studies of membrane permeabilization, electron microscopy, and soft X-ray tomography that both AMPs and ampetoids trigger extensive and rapid non-specific aggregation of intracellular biomacromolecules that correlates with microbial death. We present data demonstrating that ampetoids are "fast killers", which rapidly aggregate bacterial ribosomes in vitro and in vivo. We suggest intracellular biomass flocculation is a key mechanism of killing for cationic, amphipathic AMPs, which may explain why most AMPs require micromolar concentrations for activity, show significant selectivity for killing bacteria over mammalian cells, and finally, why development of resistance to AMPs is less prevalent than developed resistance to conventional antibiotics.

Multidrug-resistant bacteria pose a serious threat to public health worldwide. Previously, α-peptide/β-peptoid hybrid oligomers were found to display activity against Gram-negative multidrug-resistant bacteria. In the present work, the influence of hydrophobicity, fluorination, and distribution of cationic/hydrophobic residues on antimicrobial, hemolytic, and cytotoxic properties of α-peptide/β-peptoid hybrids were investigated. An array of 22 peptidomimetics was tested. Analogues with enhanced hydrophobicity were found to exhibit increased activity against Gram-positive bacteria. Incorporation of fluorinated residues into the peptidomimetics conferred increased potency against Gram-positive bacteria, while hemolytic properties and activity against Gram-negative bacteria depended on the degree and type of fluorination. Generally, shorter oligomers were less potent than the corresponding longer analogues. However, some short analogues exhibited equal or higher antimicrobial activity. The alternating hydrophobic/cationic design proved superior to other distribution patterns of cationic side chains and hydrophobic moieties., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Rapid emergence of antimicrobial resistant organisms necessitates equally rapid methods for the development of new antimicrobial compounds. Of recent interest have been mimics of antimicrobial peptides known as antimicrobial peptoids, which exhibit similar potency to the former but with improved proteolytic stability. Presented herein is a high-throughput method to screen libraries of antimicrobial peptoids immobilized on beads embedded into solid media. Termed the peptoid library agar diffusion (PLAD) assay, this assay allows for individual chemical manipulation of two identical peptoid strands. One strand can be released to diffuse out from a solid support bead and interact with the microorganism during screening. The other strand can be cleaved after screening from beads showing strong antimicrobial activity and analyzed by mass spectrometry to deconvolute the structure of the peptoid. This method was applied to a small library of peptoids to identify an antimicrobial peptoid with modest efficacy against the ESKAPE pathogens., Competing Interests: Notes The authors declare no competing financial interest.

Bacterial resistance to conventional antibiotics is a global threat that has spurred the development of antimicrobial peptides (AMPs) and their mimetics as novel anti-infective agents. While the bioavailability of AMPs is often reduced due to protease activity, the non-natural structure of AMP mimetics renders them robust to proteolytic degradation, thus offering a distinct advantage for their clinical application. We explore the therapeutic potential of N-substituted glycines, or peptoids, as AMP mimics using a multi-faceted approach that includes in silico, in vitro, and in vivo techniques. We report a new QSAR model that we developed based on 27 diverse peptoid sequences, which accurately correlates antimicrobial peptoid structure with antimicrobial activity. We have identified a number of peptoids that have potent, broad-spectrum in vitro activity against multi-drug resistant bacterial strains. Lastly, using a murine model of invasive S. aureus infection, we demonstrate that one of the best candidate peptoids at 4 mg/kg significantly reduces with a two-log order the bacterial counts compared with saline-treated controls. Taken together, our results demonstrate the promising therapeutic potential of peptoids as antimicrobial agents.

We investigated the antimicrobial activities of N-substituted glycine "peptoid" oligomers incorporating cationic and hydrophobic side chains. Head-to-tail macrocyclization was employed to enhance antimicrobial activity. Both linear and cyclic peptoids, ranging from six to ten residues, demonstrate potent antimicrobial activity against Gram-positive and Gram-negative bacteria. These peptoids do not cause significant lysis of human erythrocytes, indicating selective antimicrobial activity. Conformational ordering established upon macrocyclization is generally associated with an enhanced capacity to inhibit bacterial cell growth. Moreover, increased hydrophobic surface area also plays a role in improving antimicrobial activity. We demonstrate the potency of a cyclic peptoid in exerting antimicrobial activity against clinical strains of S. aureus while deterring the emergence of antimicrobial resistance., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The field of drug discovery and development has seen tremendous activity over the past decade to better tackle the increasing occurrence of drug-resistant bacterial infections and to alleviate some of the pressure we put on the last-resort drugs on the market. One of the new and promising drug candidates is derived from naturally occurring antimicrobial peptides. However, despite promising results in early-stage clinical trials, these molecules have faced some difficulties securing FDA approval, which can be linked to their poor metabolic stability. Hence, mimetics of these antimicrobial peptides have been suggested as new templates for antibacterial compound design, because these mimetics are resistant against degradation by proteases. This review will discuss the structural features of two different types of mimetics, β-peptides and α-peptoids, in relation to their antibacterial activity and conclude on their potential as new candidates for bacterial intervention., (© 2011 John Wiley & Sons A/S.)

The field of peptoid (i.e., N-alkylglycine) research has been thriving since the first publications on this molecular design appeared in 1992. A highly efficient and modular synthetic platform, which is compatible with automation and ready generation of combinatorial libraries, was published the same year. This has enabled the investigation of numerous compounds with this architecture, and ligands with a wide variety of interesting biological targets have thus been discovered. Furthermore, detailed biophysical and structural studies focusing on the investigation of the conformational space adopted and three-dimensional folding of these peptide mimics have been undertaken. The same is true for beta-peptides (i.e., oligomers composed of beta-amino acids). Since the first publication describing peptide mimics combining these two structural modifications [the N-alkyl-beta-alanines (beta-peptoids)] in 1998, on the other hand, the application of this backbone construct has appeared much more sparsely in the literature. The present perspective article will provide an overview of the data obtained for beta-peptoid-containing peptide mimics as well as a discussion of the future challenges associated with this type of backbone modification.

We report the creation of alkylated poly-N-substituted glycine (peptoid) mimics of antimicrobial lipopeptides with alkyl tails ranging from 5 to 13 carbons. In several cases, alkylation significantly improved the selectivity of the peptoids with no loss in antimicrobial potency. Using this technique, we synthesized an antimicrobial peptoid only 5 monomers in length with selective, broad-spectrum antimicrobial activity as potent as previously reported dodecameric peptoids and the antimicrobial peptide pexiganan.

Background: This paper describes the antimicrobial activities of 20 lysine-peptoid hybrids against a selection of clinically relevant bacteria and fungi., Methods: Minimal inhibitory concentrations were determined against methicillin-susceptible Staphylococcus aureus (ATCC 29213), methicillin-resistant S. aureus (ATCC 33591), vancomycin-intermediate S. aureus (ATCC 700699 MU50), vancomycin-resistant Enterococcus faecium (ATCC 700221), Pseudomonas aeruginosa (ATCC 27853), Salmonella typhimurium (clinical isolate), Klebsiella pneumoniae (clinical isolate), amphotericin-B-resistant C. albicans (ATCC 200955) and Cryptococcus neoformans (clinical isolate)., Results: The lysine-peptoid hybrids proved to be active against all strains tested, except K. pneumoniae. For each susceptible strain, we identified at least 4 lysine-peptoid hybrids showing excellent activity. The most active compounds displayed minimal inhibitory concentrations ranging from < or =1.6 to 6.25 microM., Conclusion: This study demonstrates that lysine-peptoid hybrids show activity against drug-resistant pathogens.

To develop a novel cell-selective antimicrobial peptide with potent anti-inflammatory activity as well as high bacterial cell selectivity, we synthesized a Leu/Lys-rich model peptide, KLW-f (KWKKLLKKfLKLfKKLLK-NH(2)) containing two Phe-peptoid residues in its middle position. KLW-f exhibited high antimicrobial activity (the MIC range: 0.5 approximately 2.0microM) against the tested six bacterial cells. In contrast, KLW-f was no cytotoxic to human red blood cells and HeLa and NIH-3T3 cells. KLW-f caused no or little dye leakage from EYPE/EYPG (7:3, w/w) vesicles (bacterial membrane-mimicking environments), indicating its bacterial-killing action is probably not due to permeabilization/disruption of bacterial cytoplasmic membranes. Furthermore, KLW-f induced a significant inhibition in LPS-stimulated NO production from mouse macrophage RAW264.7 cells at 10microg/ml. Taken together, our results suggest that KLW-f appear to have promising therapeutic potential for future development as a novel antisepsis agent as well as antimicrobial agent.