A Novel Trp-rich Model Antimicrobial Peptoid with Increased Protease Stability

Bang, Jeong Kyu; Nan, Yong Hai; Lee, Eun Kyu; Shin, Song Yub

doi:10.5012/bkcs.2010.31.9.2509

Cited by 21 publications

(13 citation statements)

References 34 publications

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“…The MICs required to completely inhibit the growth of bacteria were within the range of 2 to 64 g/ml and revealed high to moderate antimicrobial peptoid activity throughout the library compared to that of structurally similar antimicrobial peptides, such as Bac8c indolicidin and omiganan (Table 1.) (23). This is in agreement with other reported MICs of peptides and peptidomimetics that contain lysine and tryptophan side chains (3,24,25). Peptoids 1, 7, and 15 are mimics of GN-2, GN-4, and GN-6 peptides, respectively (22), and the broad-spectrum antimicrobial activities were not improved upon making these structural changes (Table 1; see also Fig.…”

Section: Resultssupporting

confidence: 79%

Structure-Activity Relationship Study of Novel Peptoids That Mimic the Structure of Antimicrobial Peptides

Mojsoska

Zuckermann

Jenssen

2015

Antimicrob Agents Chemother

116

131

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The constant emergence of new bacterial strains that resist the effectiveness of marketed antimicrobials has led to an urgent demand for and intensive research on new classes of compounds to combat bacterial infections. Antimicrobial peptoids comprise one group of potential candidates for antimicrobial drug development. The present study highlights a library of 22 cationic amphipathic peptoids designed to target bacteria. All the peptoids share an overall net charge of ؉4 and are 8 to 9 residues long; however, the hydrophobicity and charge distribution along the abiotic backbone varied, thus allowing an examination of the structure-activity relationship within the library. In addition, the toxicity profiles of all peptoids were assessed in human red blood cells (hRBCs) and HeLa cells, revealing the low toxicity exerted by the majority of the peptoids. The structural optimization also identified two peptoid candidates, 3 and 4, with high selectivity ratios of 4 to 32 and 8 to 64, respectively, and a concentration-dependent bactericidal mode of action against Gram-negative Escherichia coli. Antimicrobial peptides, also known as host defense peptides, are a class of antimicrobial agents that have long served all living organisms in combating infectious diseases by killing or inhibiting the growth of pathogens. As a class, they are relatively short (Ͻ100 amino acid residues), positively charged, amphipathic (have both hydrophobic and hydrophilic domains), and exhibit various biological activities based on their structural properties (1). Despite their high potency against a variety of clinical strains of bacteria, what limits the clinical drug development of antimicrobial peptides is their susceptibility to enzymatic degradation. Antimicrobial peptides have been subjected to various modifications in order to design novel classes of potent peptidomimetic antimicrobials with improved stability and activity profiles. Peptoids, which are oligomers of N-substituted glycines, are a new class of synthetic compounds that mimic peptide structures. The functional side chains of commercial availability in peptoids are attached to the nitrogen rather than the ␣-carbon in the peptide counterparts (Fig. 1) through a two-step process (see Fig. S1 in the supplemental material). Peptoids circumvent proteolytic susceptibility while retaining the beneficial features of antimicrobial peptides (2-4); hence, they are promising structures for antimicrobial drug development. For Ͼ15 years, research on peptoid synthesis and application has increased dramatically due to their potential biological applications as antimicrobials (5-7), molecular transporters (8, 9), and more recently as anticancer agents (10) and nanostructured materials (11,12).In the efforts to increase the effectiveness of antimicrobial peptides and their mimetics, two key structural elements that decide their overall antimicrobial activity are charge and hydrophobicity. These two elements contribute with different physiochemical properties to the interaction of peptides wi...

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Section: Resultssupporting

confidence: 79%

Structure-Activity Relationship Study of Novel Peptoids That Mimic the Structure of Antimicrobial Peptides

Mojsoska

Zuckermann

Jenssen

2015

Antimicrob Agents Chemother

116

131

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“…Both peptoids have relatively short sequences (9 residues, Fig. 1 ) and exhibit MIC ( ≤ 22.2 μM) values that are comparable to that of the antimicrobial peptide indolicidin ( Table 1 ) and are within the range of other antimicrobial peptoids reported in the literature 8 17 .…”

Section: Resultssupporting

confidence: 57%

Peptoids successfully inhibit the growth of gram negative E. coli causing substantial membrane damage

Mojsoska

Carretero

Larsen

et al. 2017

Sci Rep

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Peptoids are an alternative approach to antimicrobial peptides that offer higher stability towards enzymatic degradation. It is essential when developing new types of peptoids, that mimic the function of antimicrobial peptides, to understand their mechanism of action. Few studies on the specific mechanism of action of antimicrobial peptoids have been described in the literature, despite the plethora of studies on the mode of action of antimicrobial peptides. Here, we investigate the mechanism of action of two short cationic peptoids, rich in lysine and tryptophan side chain functionalities. We demonstrate that both peptoids are able to cause loss of viability in E. coli susceptible cells at their MIC (16–32 μg/ml) concentrations. Dye leakage assays demonstrate slow and low membrane permeabilization for peptoid 1, that is still higher for lipid compositions mimicking bacterial membranes than lipid compositions containing Cholesterol. At concentrations of 4 × MIC (64–128 μg/ml), pore formation, leakage of cytoplasmic content and filamentation were the most commonly observed morphological changes seen by SEM in E. coli treated with both peptoids. Flow cytometry data supports the increase of cell size as observed in the quantification analysis from the SEM images and suggests overall decrease of DNA per cell mass over time.

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“…Bang et al reported the conversion of a Trp-rich peptide, H-KLWKKWKKWLK-NH 2 , into the corresponding protease-stable peptoid without loss of potency or increase in hemolytic properties [ 181 ]. Interestingly, the killing kinetics of the Trp-rich peptide and the peptoid analog were compared at 8 μM (1 or 2 × MIC) against E. coli and S. aureus , and it was found that the bactericidal rate of the peptoid (60 min) was slower than that of the peptide (30 min), indicating different killing mechanisms.…”

Section: Peptidomimeticsmentioning

confidence: 99%

Advances in Development of Antimicrobial Peptidomimetics as Potential Drugs

2017

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The rapid emergence of multidrug-resistant pathogens has evolved into a global health problem as current treatment options are failing for infections caused by pan-resistant bacteria. Hence, novel antibiotics are in high demand, and for this reason antimicrobial peptides (AMPs) have attracted considerable interest, since they often show broad-spectrum activity, fast killing and high cell selectivity. However, the therapeutic potential of natural AMPs is limited by their short plasma half-life. Antimicrobial peptidomimetics mimic the structure and biological activity of AMPs, but display extended stability in the presence of biological matrices. In the present review, focus is on the developments reported in the last decade with respect to their design, synthesis, antimicrobial activity, cytotoxic side effects as well as their potential applications as anti-infective agents. Specifically, only peptidomimetics with a modular structure of residues connected via amide linkages will be discussed. These comprise the classes of α-peptoids (N-alkylated glycine oligomers), β-peptoids (N-alkylated β-alanine oligomers), β3-peptides, α/β3-peptides, α-peptide/β-peptoid hybrids, α/γ N-acylated N-aminoethylpeptides (AApeptides), and oligoacyllysines (OAKs). Such peptidomimetics are of particular interest due to their potent antimicrobial activity, versatile design, and convenient optimization via assembly by standard solid-phase procedures.

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A Novel Trp-rich Model Antimicrobial Peptoid with Increased Protease Stability

Cited by 21 publications

References 34 publications

Structure-Activity Relationship Study of Novel Peptoids That Mimic the Structure of Antimicrobial Peptides

Structure-Activity Relationship Study of Novel Peptoids That Mimic the Structure of Antimicrobial Peptides

Peptoids successfully inhibit the growth of gram negative E. coli causing substantial membrane damage

Advances in Development of Antimicrobial Peptidomimetics as Potential Drugs

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