Sequence-specific polypeptoids: A diverse family of heteropolymers with stable secondary structure

Kirshenbaum, Kent; Barron, Annelise E.; Goldsmith, Richard; Armand, Philippe; Bradley, Erin K.; Truong, Kiet T. V.; Dill, Ken A.; Cohen, Fred E.; Zuckermann, Ronald N.

doi:10.1073/pnas.95.8.4303

Cited by 455 publications

(405 citation statements)

References 33 publications

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“…The synthesis were performed according to the improved method by Kirshenbaum et al 22 Briefly, after removal of the first Fmoc group, the following 90-min monomer addition cycle was performed by a robotic synthesizer and repeated until the desired length was obtained. The amino resin was bromoacetylated by adding 830 ml of 1.2 M bromoacetic acid in N,N-dimethyl formamide and 200 ml of N,N-diisopropyl carbodiimide.…”

Section: Computational Design and Synthesis Of Cd28-binding Peptoidsmentioning

confidence: 99%

Blockade of CD28 by a synthetical peptoid inhibits T-cell proliferation and attenuates graft-versus-host disease

Zhu

Gao

et al. 2010

Cell Mol Immunol

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CD28 is one of the costimulatory molecules crucial for T-cell activation and thus has become an attractive target for therapeutic immunomodulation. Conventional strategies for blocking CD28 activity using monoclonal antibodies, Fab fragments, antagonistic peptide and fusion proteins, have apparent disadvantages such as inherent immunogenicity, unwanted Fc signaling, poor tissue penetration and bioinstability. Recent research has been directed toward the creation of non-natural, sequence-specific biomimetic oligomers with bioinspired structures that capture the amino-acid interface of the targeted proteins. One such family of molecules is the poly-N-substituted glycines or peptoids, which have close structural similarity to peptides but are essentially invulnerable to protease degradation. To screen for peptoids that specifically target CD28, we first designed and chemically synthesized 19 candidate peptoids based on molecular modeling and docking. Using the phage-displaying system that expresses the extracellular domain of the CD28 homodimer and contains the core B7-binding motif, a peptoid (No. 9) with a molecular formula of C 21 H 29 N 3 O 7 , was identified to display the highest binding activity to CD28. This peptoid not only inhibited the lymphocyte proliferation in vitro, but suppressed immunoresponses against alloantigens in vivo, and attenuated the graft-versus-host disease in a mouse bone-marrow transplantation model. These results suggested that peptoids targeting CD28 are effective agents for blocking the CD28-mediated costimulation and suitable for development of novel therapeutic approaches for diseases involving this pathway.

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Section: Computational Design and Synthesis Of Cd28-binding Peptoidsmentioning

confidence: 99%

Blockade of CD28 by a synthetical peptoid inhibits T-cell proliferation and attenuates graft-versus-host disease

Zhu

Gao

et al. 2010

Cell Mol Immunol

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“…The peptoid products were cleaved from the solid support and purified before use as catalysts for the OKR of 1-phenylethanol. CD spectra confirmed the existence of secondary structure, resembling a polyproline type I helix (13), in catalytic peptoids 1S-4S. Peptoids 1S and 1R exhibited CD ellipticities ( ) of equal magnitude with opposite sign, indicating the formation of rightand left-handed helices, respectively, with an equivalent degree of helical character.…”

Section: Synthesis and Characterization Of Peptoids Incorporating Temmentioning

confidence: 56%

“…Herein, we evaluate peptoids-oligomers of N-substituted glycine-as a synthetically tractable platform for the facile construction of enantioselective catalysts. These oligomers form unique, well-defined, and thermally stable helical architectures (13)(14)(15)(16) that enable the covalent attachment of achiral catalytic centers at prescribed locations on a robust chiral peptoid scaffold for optimization of catalytic enantioselectivity and overall performance.…”

mentioning

confidence: 99%

Folded biomimetic oligomers for enantioselective catalysis

Maayan

Ward

Kirshenbaum

2009

Proc. Natl. Acad. Sci. U.S.A.

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186

143

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Many naturally occurring biopolymers (i.e., proteins, RNA, DNA) owe their unique properties to their well-defined three-dimensional structures. These attributes have inspired the design and synthesis of folded architectures with functions ranging from molecular recognition to asymmetric catalysis. Among these are synthetic oligomeric peptide (''foldamer'') mimics, which can display conformational ordering at short chain lengths. Foldamers, however, have not been explored as platforms for asymmetric catalysis. This report describes a library of synthetic helical ''peptoid'' oligomers that enable enantioselective transformations at an embedded achiral catalytic center, as illustrated by the oxidative kinetic resolution of 1-phenylethanol. In an investigation aimed at elucidating key structure-function relationships, we have discovered that the enantioselectivity of the catalytic peptoids depends on the handedness of the asymmetric environment derived from the helical scaffold, the position of the catalytic center along the peptoid backbone, and the degree of conformational ordering of the peptoid scaffold. The transfer of chiral information from a folded scaffold can enable the use of a diverse assortment of embedded achiral catalytic centers, promising a generation of synthetic foldamer catalysts for enantioselective transformations that can be performed under a broad range of reaction environments.catalyst ͉ foldamer ͉ oxidative kinetic resolution ͉ peptoid T he unique capabilities of biopolymers, which stem from their well-defined three-dimensional structures, have been a source of inspiration for the design and synthesis of functional chemical systems (1). A variety of strategies have been explored for de novo construction of modular catalysts that enable chemical selectivity, regioselectivity, or enantioselectivity as a consequence of their structural organization. For example, synthetic peptides equipped with catalytic artificial amino acid groups or transition metal sites have been demonstrated to be effective enantioselective catalysts due to the proximity of the catalytic sites to the asymmetric environment created by their backbone (2-4). Similarly, it has been reported that nucleic acids can be used as chiral scaffolds for asymmetric synthesis and catalysis (5, 6). A recent investigation of DNA-based asymmetric catalysis relies on the noncovalent association of an achiral metal catalyst at unspecified sites along a DNA backbone, creating a chiral environment about the catalytic center that results in enantioselective transformations (7,8). Despite these advances, there remains a need for robust systems that permit rational design of versatile sequences and facile synthesis of libraries for high-throughput screening and optimization of catalytic performance.In living systems, biopolymer catalysts have evolved to accelerate specific biologically relevant transformations. In contrast, synthetic catalysts must often be designed for nonbiological transformations to be performed in abiotic solvents, pH regime...

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“…As a result, the global conformations of polypeptoids are strongly dependent on the N-substituent structures, giving rise to random coils or well-defined secondary structures [eg, polyproline I (PPI) helix [1][2][3][4][5][6] and R-sheets] [7][8][9][10][11][12] that are reminiscent of those of polypeptides. The polypeptoid backbone containing tertiary amide linkages is highly polar and hydrophilic.…”

Section: Introductionmentioning

confidence: 99%

Polypeptoid polymers: Synthesis, characterization, and properties

et al. 2017

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Polypeptoids, a class of peptidomimetic polymers, have emerged at the forefront of macromolecular and supramolecular science and engineering as the technological relevance of these polymers continues to be demonstrated. The chemical and structural diversity of polypeptoids have enabled access to and adjustment of a variety of physicochemical and biological properties (eg, solubility, charge characteristics, chain conformation, HLB, thermal processability, degradability, cytotoxicity and immunogenicity). These attributes have made this synthetic polymer platform a potential candidate for various biomedical and biotechnological applications. This review will provide an overview of recent development in synthetic methods to access polypeptoid polymers with well-defined structures and highlight some of the fundamental physicochemical and biological properties of polypeptoids that are pertinent to the future development of functional materials based on polypeptoids. | I N TR ODU C TI ONPolypeptoids composed of N-substituted polyglycine backbones are structural mimics of polypeptides ( Figure 1). Because of N-substitution, polypeptoids lack stereogenic centers and hydrogen bonding interactions along the main chains, in sharp contrast to polypeptides.As a result, the global conformations of polypeptoids are strongly dependent on the N-substituent structures, giving rise to random coils or well-defined secondary structures [eg, polyproline I (PPI) helix [1][2][3][4][5][6] and R-sheets] [7][8][9][10][11][12] that are reminiscent of those of polypeptides. The polypeptoid backbone containing tertiary amide linkages is highly polar and hydrophilic. The physicochemical properties of polypeptoids can be tailored by the N-substituent structures, enabling control over the hydrophilicity and lipophilicity balance (HLB), charge characteristics, [13,14] backbone conformation, [1][2][3][4][5][6][7][8][9][10][11][12] solubility, [15][16][17][18][19][20] thermal and crystallization properties of the polypeptoids. [21][22][23][24] Without extensive hydrogen bonding, polypeptoids are thermally processable similar to conventional thermoplastics, [20][21][22][23][24] whereas polypeptides undergo thermal degradation before they can be melt-processed due to the extensive hydrogen bonding interactions. While polypeptoids exhibited enhanced proteolytic stability relative to peptides, [25,26] they can be oxidatively degraded under conditions that mimic tissue inflammation, [27] suggesting their potential in vivo uses as biodegradable materials.Recent advances in the controlled polymerization methods have enabled access to a suite of structurally well-defined polypeptoids with various N-substituent structures and molecular architectures, setting the stage for the future development of polypeptoid materials for various targeted applications. Several review articles on the synthesis, properties, and application of polypeptoids for biomedical or nonbiomedical uses have been published in recent years. [28][29][30][31][32] As a result, this...

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Sequence-specific polypeptoids: A diverse family of heteropolymers with stable secondary structure

Cited by 455 publications

References 33 publications

Blockade of CD28 by a synthetical peptoid inhibits T-cell proliferation and attenuates graft-versus-host disease

Blockade of CD28 by a synthetical peptoid inhibits T-cell proliferation and attenuates graft-versus-host disease

Folded biomimetic oligomers for enantioselective catalysis

Polypeptoid polymers: Synthesis, characterization, and properties

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