Versatile Oligo(
            <i>N</i>
            ‐Substituted) Glycines: The Many Roles of Peptoids in Drug Discovery

Due to the pivotal roles that protein-protein interactions play in a plethora of biological processes, the design of therapeutic agents targeting these interactions has become an attractive and important area of research. The development of such agents is faced with a variety of challenges. Nevertheless, considerable progress has been made in the design of proteomimetics capable of disrupting protein-protein interactions. Those inhibitors based on molecular scaffold designs hold considerable interest because of the ease of variation in regard to their displayed functionality. In particular, protein surface mimetics, alpha-helical mimetics, beta-sheet/beta-strand mimetics, as well as beta-turn mimetics have successfully modulated protein-protein interactions involved in such diseases as cancer and HIV. In this review, current progress in the development of molecular scaffolds designed for the disruption of protein-protein interactions will be discussed with an emphasis on those active against biological targets.

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“…Peptoid helices have found use in a variety of applications outside protein-protein interactions [57][58][59].…”

Section: -Peptides and Peptoid Helical Mimeticsmentioning

confidence: 99%

Scaffolds for Blocking Protein-Protein Interactions

Hershberger¹,

Lee²,

Chmielewski

2007

CTMC

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“…1 Peptoids are attractive for at least three reasons, including (1) their ease of synthesis, (2) their proteolytic stability, and (3) the wide variety of non-native functionality that can be incorporated into their amide side chains. These features have prompted the development of peptoids as tools to probe a diverse range of biological processes and as therapeutic agents.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Characterization of Nitroaromatic Peptoids: Fine Tuning Peptoid Secondary Structure through Monomer Position and Functionality

2009

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N-substituted glycine oligomers, or peptoids, have emerged as an important class of foldamers for the study of biomolecular interactions and for potential use as therapeutic agents. However, the design of peptoids with well-defined conformations a priori remains a formidable challenge. New approaches are required to address this problem, and the systematic study of the role of individual monomer units in the global peptoid folding process represents one strategy. Here, we report our efforts toward this approach through the design, synthesis, and characterization of peptoids containing nitroaromatic monomer units. This work required the synthesis of a new chiral amine building block, (S)-1-(2-nitrophenyl)ethanamine (s2ne), which could be readily installed into peptoids using standard solid-phase peptoid synthesis techniques. We designed a series of peptoid nonamers that allowed us to probe the effects of this relatively electron-deficient and sterically encumbered α-chiral side chain on peptoid structure, namely, the peptoid threaded loop and helix. Circular dichroism (CD) spectroscopy of the peptoids revealed that the nitroaromatic monomer has a significant effect on peptoid secondary structure. Specifically, the threaded loop structure was disrupted in a nonamer containing alternating N-(S)-1-phenylethylglycine (Nspe) and Ns2ne monomers, and the major conformation was helical instead. Indeed, placement of a single Ns2ne at the N-terminal position of (Nspe)9 resulted in a destabilized form of the threaded loop structure relative to the homononamer (Nspe)9. Conversely, we observed that incorporation of N-(S)-1-(4-nitrophenyl)ethylglycine (Nsnp, a para-nitro monomer) at the N-terminal position stabilized the threaded loop structure relative to (Nspe)9. Additional experiments revealed that nitroaromatic side chains can influence peptoid nonamer folding by modulating the strength of key intramolecular hydrogen bonds in the peptoid threaded loop structure. Steric interactions were also implicated for the Ns2ne monomer. Overall, this study provides further evidence that aromatic side chain structure, even if perturbed in a single monomer unit, can strongly influence local peptoid backbone conformation.

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“…However, peptides largely have not been developed for clinical use, because peptide therapeutics are costly and generally have poor oral bioavailability, short half-life in the body, and/or elicit an immune response. 17 These problems create a great opportunity to develop peptoid therapeutics, as peptoids have enhanced proteolytic stability relative to α-peptides and can be synthesized on large scale more cost effectively than peptides. 11 In addition, peptoids can adopt folded conformations analogous to α-peptides—as outlined above, there exist robust strategies for the stabilization of peptoid helices 31 and recent reports describe methods for the stabilization of loops 32,35 and turns 25,37 in peptoids.…”

Section: Peptoids That Mimic Biologically Active Peptidesmentioning

confidence: 99%

“…A comprehensive review of peptoids in drug discovery, detailing peptoid synthesis, biological applications, and structural studies, was published by Barron, Kirshenbaum, Zuckermann, and co-workers in 2004. 17 Since that time, significant advances have been made in these areas, and new applications for peptoids have emerged. In addition, new peptoid secondary structural motifs have been reported, as well as strategies to stabilize those structures.…”

Section: Introductionmentioning

confidence: 99%

Structure–function relationships in peptoids: Recent advances toward deciphering the structural requirements for biological function

2009

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Oligomers of N-substituted glycine, or peptoids, are versatile tools to probe biological processes and hold promise as therapeutic agents. An underlying theme in the majority of recent peptoid research is the connection between peptoid function and peptoid structure. For certain applications, well-folded peptoids are essential for activity, while unstructured peptoids appear to suffice, or even are superior, for other applications. Currently, these structure-function connections are largely made after the design, synthesis, and characterization process. However, as guidelines for peptoid folding are elucidated and the known biological activities are expanded, we anticipate these connections will provide a pathway toward the de novo design of functional peptoids. In this perspective, we review several of the peptoid structure-function relationships that have been delineated over the past five years.

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Versatile Oligo( N ‐Substituted) Glycines: The Many Roles of Peptoids in Drug Discovery

Cited by 47 publications

References 0 publications

Scaffolds for Blocking Protein-Protein Interactions

Scaffolds for Blocking Protein-Protein Interactions

Synthesis and Characterization of Nitroaromatic Peptoids: Fine Tuning Peptoid Secondary Structure through Monomer Position and Functionality

Structure–function relationships in peptoids: Recent advances toward deciphering the structural requirements for biological function

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