Small Molecular Antibacterial Peptoid Mimics: The Simpler the Better!

Ghosh, Chandradhish; Manjunath, Goutham B.; Akkapeddi, Padma; Yarlagadda, Venkateswarlu; Hoque, Jiaul; Uppu, Divakara S. S. M.; Konai, Mohini M.; Haldar, Jayanta

doi:10.1021/jm401680a

Cited by 176 publications

(189 citation statements)

References 41 publications

(74 reference statements)

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“…The set of antibacterial peptoids known as ampetoids have high potency against bacteria [36][37][38][39]. Their structure--activity and structure--hemolytic side-effect relationships have been investigated experimentally in detail.…”

Section: Antibacterial Applicationsmentioning

confidence: 99%

An overview of peptide and peptoid foldamers in medicinal chemistry

Mándity¹,

Fülöp²

2015

Expert Opinion on Drug Discovery

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Various new foldamers have been created with a range of structures and biological applications. Membrane-acting antibacterial foldamers have been introduced. A general property of these structures is their amphiphilic nature. The amphiphilicity can be stationary or induced by the membrane binding. Cell-penetrating foldamers have been described which serve as cargo molecules, and foldamers have been used as autophagy inducers. Anti-Alzheimer compounds too have been created and the greatest breakthrough was attained via the modification of protein-protein interactions. This can serve as the chemical and pharmaceutical basis for the relevance of foldamers in the future.

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Section: Antibacterial Applicationsmentioning

confidence: 99%

An overview of peptide and peptoid foldamers in medicinal chemistry

Mándity¹,

Fülöp²

2015

Expert Opinion on Drug Discovery

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“…These two elements contribute with different physiochemical properties to the interaction of peptides with bacterial and mammalian membranes in which hydrophobicity, in particular, directs the degree of peptide partitioning into the lipid bilayer (6,(13)(14)(15)(16). With this in mind, the mechanism of action is greatly related to either the disruption of bacterial membranes through pore formation or passage through the bacterial membranes and targeting of cytoplasmic compartments (17).…”

mentioning

confidence: 99%

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

Mojsoska

Zuckermann

Jenssen

2015

Antimicrob Agents Chemother

109

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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“…† The conformation of the D-peptides was also conrmed to be opposite of the Lpeptides, consistent with the different conformations of the amino acids used. 45 Thus, the presence of a R 9 segment in our peptide vectors induced an a-helical conrmation in the secondary structure of our chimeric peptide vectors.…”

Section: Measurementsmentioning

confidence: 79%

The structure and configuration changes of multifunctional peptide vectors enhance gene delivery efficiency

et al. 2018

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We designed a series of peptide vectors that contain functional fragments with the goal of enhancing cellular internalization and gene transfection efficiency. The functional fragments included a cellpenetrating peptide (R 9 ), a cationic amphiphilic a-helical peptide [(LLKK) 3 -H 6 or (LLHH) 3 ], a stearyl moiety, and cysteine residues. Vectors were also synthesized with D-type amino acids to improve their proteolytic stability. The conformations, particle sizes, and zeta potentials for complexes of these peptides with pGL3 plasmid DNA were characterized by circular dichroism and dynamic light scattering.In addition, cellular uptake of the peptide/DNA complexes and gene transfection efficiency were investigated with fluorescence-activated cell sorting and confocal laser-scanning microscopy. Greater transfection efficiency was achieved with the vectors containing the R 9 segment, and the efficiency was greater than Lipo2000. In addition, the D-type C 18 -c(llkk) 3 ch 6 -r 9 had about 7 times and 5.5 times the transfection efficiency of Lipo2000 in 293T cells and NIH-3T3 cells at the N/P ratio of 6, respectively. Overall, the multifunctional peptide gene vectors containing the R 9 segment exhibited enhanced cellular internalization, a high gene transfection efficiency, and low cytotoxicity.

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Small Molecular Antibacterial Peptoid Mimics: The Simpler the Better!

Cited by 176 publications

References 41 publications

An overview of peptide and peptoid foldamers in medicinal chemistry

An overview of peptide and peptoid foldamers in medicinal chemistry

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

The structure and configuration changes of multifunctional peptide vectors enhance gene delivery efficiency

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