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

Abstract

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...

Structural Modeling and Conformational Analysis of Aromatic Polypeptoid Models Confined to Different Environmental Conditions

“…The amide bond geometry was found to be degenerate with ω = 0 ± 20° and 180 ± 20° in model dipepoids. In peptoids of the type Ac-(Nphe) 7 160° respectively and Nspe peptoids were more stable than Nrpe peptoids with increasing chain length. Stability of these states has been explained in terms of various non-covalent interactions like carbonyl-carbonyl, carbonyl-aromatic and stacking interactions.…”

“…Also, the rapid room temperature synthesis of a wide variety of N-aryl glycine-rich peptoid oligomers with both electron-withdrawing and donating substituents is possible in good yields through silver-mediated reactions [4]. Thus, peptoids are extensively used as peptide mimics particularly of antimicrobial peptides [5][6][7], antibacterial magainin peptides [8] and lung surfactant proteins [9]. Their cell penetrating properties [10] and antifouling action on surfaces [11][12][13][14] and as drug and gene delivery agents are also being exploited [15,16].…”

An Efficient Method for the Synthesis of Peptoids with Mixed Lysine-type/Arginine-type Monomers and Evaluation of Their Anti-leishmanial Activity

“…Peptoids are increasingly being studied within the chemical biology and medicinal chemistry fields in applications such as novel therapeutics [3][4][5] , cell delivery agents 18,20 and diagnostic tools. 29 Typically, these sequences are cationic to provide a degree of selectivity for the pathogen over mammalian cells, the ability to penetrate through cell membranes and also aid solubility in aqueous systems.…”

“…Peptoids have been shown to have promising activities against a wide range of Gram negative bacteria, Gram positive bacterial and fungal species that are comparable to many known antimicrobial peptides. [3][4][5][6][7][8][9] In our work, peptoids have been used as novel anti-infective compounds for treatment of the neglected tropical disease leishmaniasis. 5,10 Leishmaniasis is endemic in more than 80 countries worldwide and it is estimated that over 12 million people are infected globally.…”

“…[12][13][14][15][16] In these antimicrobial applications, peptoids are often designed to be amphipathic with a mixture of cationic and hydrophobic monomers. 3,4 This can give peptoids a degree of selectivity towards bacterial cells, reduce toxicity to mammalian cells, and to improve their activity as molecular transporters. [17][18][19][20] The majority of the anti-infective peptoids in the literature contain cationic side chains that are exclusively comprised of either amino functionalized lysine-type monomers or arginine-type residues.…”