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In this work Selwood and co-workers describe an elegant demonstration of how small molecules can efficiently mimic an α-helix, in this case to generate a very small cell penetrating peptide (CPP). The molecules reported are shown to deliver a variety of biomolecules to the interior of cells.
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Okuyama M., Laman H., Kingsbury S.R., Visintin C., Leo E., Eward K.L., Stoeber K., Boshoff C., Williams G.H., and Selwood D.L. Small-molecule mimics of an α-helix for efficient transport of proteins into cells. Nat Methods 4 (2007) 153-159. In this work Selwood and co-workers describe an elegant demonstration of how small molecules can efficiently mimic an α-helix, in this case to generate a very small cell penetrating peptide (CPP). The molecules reported are shown to deliver a variety of biomolecules to the interior of cells.
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This paper describes a clever method to quantify the relative cell permeability of peptides and peptidomimetics such as peptoids. In this assay, the compound is conjugated to dexamethasone and incubated with a cell containing three plasmids. One of these harbors a Gal4 DNA-binding domain and a VP16 transactivation domain that is bound and activated by dexamethasone. The other two contain a Gal4-responsive firefly luciferase reporter gene and an independently expressed Renilla reniformis luciferase, respectively. The concentration of compound inside the cell is measured by quantifying the ratio of luciferase output from these two reporter plasmids.
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Kwon Y.U., and Kodadek T. Quantitative evaluation of the relative cell permeability of peptoids and peptides. J Am Chem Soc 129 (2007) 1508-1509. This paper describes a clever method to quantify the relative cell permeability of peptides and peptidomimetics such as peptoids. In this assay, the compound is conjugated to dexamethasone and incubated with a cell containing three plasmids. One of these harbors a Gal4 DNA-binding domain and a VP16 transactivation domain that is bound and activated by dexamethasone. The other two contain a Gal4-responsive firefly luciferase reporter gene and an independently expressed Renilla reniformis luciferase, respectively. The concentration of compound inside the cell is measured by quantifying the ratio of luciferase output from these two reporter plasmids.
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This study utilized a unique strategy of appending a purine analog to each member of a peptoid library to select for inhibitors of the 19S regulatory particle of the proteome. Significantly, the resulting compound was able to enter cells and antagonize 26S-mediated proteolytic degradation of the p27 protein.
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Lim H.S., Archer C.T., and Kodadek T. Identification of a peptoid inhibitor of the proteasome 19S regulatory particle. J Am Chem Soc 129 (2007) 7750-7751. This study utilized a unique strategy of appending a purine analog to each member of a peptoid library to select for inhibitors of the 19S regulatory particle of the proteome. Significantly, the resulting compound was able to enter cells and antagonize 26S-mediated proteolytic degradation of the p27 protein.
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A peptoid found to have high affinity for the KIX domain of the CREB-binding protein was linked to the known DNA-binding hairpin polyamide ImPy7 to generate a synthetic transcription factor mimic. This cell-permeable construct is the first of its class able to activate endogenous genes in live cells.
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Xiao X., Yu P., Lim H.-S., Sikder D., and Kodadek T. A cell-permeable synthetic transcription factor mimic. Angew Chem Int Ed 46 (2007) 2865-2868. A peptoid found to have high affinity for the KIX domain of the CREB-binding protein was linked to the known DNA-binding hairpin polyamide ImPy7 to generate a synthetic transcription factor mimic. This cell-permeable construct is the first of its class able to activate endogenous genes in live cells.
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L. The paper provides a complete series of experiments including alanine and hydrophile scanning that will likely prove useful for targeting other protein-binding pockets in a similar manner if a single scaffold does not suffice
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Hara T., Durell S.R., Myers M.C., and Appella D.H. Probing the structural requirements of peptoids that inhibit hdm2-p53 interactions. J Am Chem Soc 128 (2006) 1995-2004. A peptoid previously identified as an inhibitor of the p53·hDM2 interaction was optimized to improve its solubility and binding properties, providing insight into the general considerations for designing peptoid inhibitors.
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This work used a rigid biaryl scaffold designed to target the ligand-binding domain of the estrogen receptor by providing a mimic of the positioning of residues in a known coactivator protein. Competitive binding experiments demonstrated that the identified inhibitors could in fact compete directly with the coactivator for its binding site.
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Becerril J., and Hamilton A.D. Helix mimetics as inhibitors of the interaction of the estrogen receptor with coactivator peptides. Angew Chem Int Ed 46 (2007) 4471-4473. This work used a rigid biaryl scaffold designed to target the ligand-binding domain of the estrogen receptor by providing a mimic of the positioning of residues in a known coactivator protein. Competitive binding experiments demonstrated that the identified inhibitors could in fact compete directly with the coactivator for its binding site.
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1 integrin. A potent inhibitor identified through an ELISA assay was able to inhibit the interaction between the two proteins in cells and was shown to target an allosteric-binding site, providing an alternative strategy for targeting similar domains.
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1 integrin. A potent inhibitor identified through an ELISA assay was able to inhibit the interaction between the two proteins in cells and was shown to target an allosteric-binding site, providing an alternative strategy for targeting similar domains.
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Yin H., Frederick K.K., Liu D., Wand A.J., and DeGrado W.F. Arylamide derivatives as peptidomimetic inhibitors of calmodulin. Org Lett 8 (2006) 223-225. The authors describe a group of arylamide derivatives designed to mimic a calmodulin-binding helical peptide. Fluorescence polarization and NMR experiments were used to demonstrate the inhibitory activity and binding site of the inhibitors.
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Yin H., Slusky J.S., Berger B.W., Walters R.S., Vilaire G., Litvinov R.I., Lear J.D., Caputo G.A., Bennett J.S., and DeGrado W.F. Computational design of peptides that target transmembrane helices. Science (Washington, DC, US) 315 (2007) 1817-1822
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Yin, H.1
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Litvinov, R.I.6
Lear, J.D.7
Caputo, G.A.8
Bennett, J.S.9
DeGrado, W.F.10
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49
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Cyclic peptoids
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Cyclic peptoids were prepared rapidly and in high efficiency with chain lengths ranging from 4 to 20 residues. The resulting structures revealed the ability of peptoids to assume reverse-turns similar to those found in natural peptides.
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Shin S.B.Y., Yoo B., Todaro L.J., and Kirshenbaum K. Cyclic peptoids. J Am Chem Soc 129 (2007) 3218-3225. Cyclic peptoids were prepared rapidly and in high efficiency with chain lengths ranging from 4 to 20 residues. The resulting structures revealed the ability of peptoids to assume reverse-turns similar to those found in natural peptides.
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Shin, S.B.Y.1
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Kirshenbaum, K.4
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50
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Introduction of a triazole amino acid into a peptoid oligomer induces turn formation in aqueous solution
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Pokorski J.K., Jenkins L.M.M., Feng H.Q., Durell S.R., Bai Y.W., and Appella D.H. Introduction of a triazole amino acid into a peptoid oligomer induces turn formation in aqueous solution. Org Lett 9 (2007) 2381-2383
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Pokorski, J.K.1
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Bai, Y.W.5
Appella, D.H.6
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51
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A threaded loop conformation adopted by a family of peptoid nonamers
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9 adopts a unique, hydrogen bond facilitated threaded-loop conformation in acetontrile, exemplifying the ability of peptoids to adopt complex three-dimensional structures.
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9 adopts a unique, hydrogen bond facilitated threaded-loop conformation in acetontrile, exemplifying the ability of peptoids to adopt complex three-dimensional structures.
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(2006)
J Am Chem Soc
, vol.128
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Huang, K.1
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Patch, J.A.4
Kirshenbaum, K.5
Zuckermann, R.N.6
Barron, A.E.7
Radhakrishnan, I.8
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53
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Tuning peptoid secondary structure with pentafluoroaromatic functionality: A new design paradigm for the construction of discretely folded peptoid structures
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This work explored the role of pentafluoroaromatic side-chains in favoring peptoid helicity by destabilizing backbone hydrogen bonds. The ability to of this group to enhance π-stacking was dismissed in favor of its effect on backbone electrostatics.
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Gorske B.C., and Blackwell H.E. Tuning peptoid secondary structure with pentafluoroaromatic functionality: A new design paradigm for the construction of discretely folded peptoid structures. J. Am. Chem. Soc. 128 (2006) 14378-14387. This work explored the role of pentafluoroaromatic side-chains in favoring peptoid helicity by destabilizing backbone hydrogen bonds. The ability to of this group to enhance π-stacking was dismissed in favor of its effect on backbone electrostatics.
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Gorske, B.C.1
Blackwell, H.E.2
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Toward β-peptide tertiary structure: Self-association of an amphiphilic 14-helix in aqueous solution
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Raguse T.L., Lai J.R., LePlae P.R., and Gellman S.H. Toward β-peptide tertiary structure: Self-association of an amphiphilic 14-helix in aqueous solution. Org Lett 3 (2001) 3963-3966
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Gellman, S.H.4
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56
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Seebach D., Abele S., Gademann K., and Jaun B. Pleated sheets and turns of β-peptides with proteinogenic side chains. Angew Chem Int Ed 38 (1999) 1595-1597
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Seebach, D.1
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3hHis building blocks: Evidence from CD measurements
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3hHis building blocks: Evidence from CD measurements. Helv Chim Acta 86 (2003) 2653-2661
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2+ complexation - On the way to β-peptidic zinc fingers?
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2+. The design principles that are incorporated into this β-hexadecapeptide are a culmination of virtually all of the previous efforts directed at developing β-peptide structure.
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2+. The design principles that are incorporated into this β-hexadecapeptide are a culmination of virtually all of the previous efforts directed at developing β-peptide structure.
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(2006)
Helv Chim Acta
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Lelais, G.1
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Flogel, O.5
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Campo, M.7
Wortmann, A.8
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60
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Peptide velcro - design of a heterodimeric coiled-coil
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Oshea E.K., Lumb K.J., and Kim P.S. Peptide velcro - design of a heterodimeric coiled-coil. Curr Biol 3 (1993) 658-667
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Toward β-amino acid proteins: A cooperatively folded β-peptide quaternary structure
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3-peptides that oligomerize in solution at micromolar concentrations and with a discrete, octameric stoichiometry.
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3-peptides that oligomerize in solution at micromolar concentrations and with a discrete, octameric stoichiometry.
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J Am Chem Soc
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Qiu, J.X.1
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The packing of α-helices - simple coiled-coils
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Crick F.H.C. The packing of α-helices - simple coiled-coils. Acta Cryst 6 (1953) 689-697
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Goodman JL, Petersson EJ, Daniels DS, Qiu JX, Schepartz A: Biophysical and structural characterization of a robust octameric β-peptide bundle. J Am Chem Soc 2007, in press.
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66
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X-ray structure of the Gcn4 leucine zipper, a 2-stranded, parallel coiled coil
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Oshea E.K., Klemm J.D., Kim P.S., and Alber T. X-ray structure of the Gcn4 leucine zipper, a 2-stranded, parallel coiled coil. Science (Washington, DC, US) 254 (1991) 539-544
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67
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Hydrogen bonds in molecular assemblies of natural, synthetic and 'designer' peptides
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Karle I.L. Hydrogen bonds in molecular assemblies of natural, synthetic and 'designer' peptides. J Mol Struct 474 (1999) 103-112
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(1999)
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Karle, I.L.1
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Peptide hybrids containing α- and β-amino acids: Structure of a decapeptide β-hairpin with two facing β-phenylalanine residues
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Karle I.L., Gopi H.N., and Balaram P. Peptide hybrids containing α- and β-amino acids: Structure of a decapeptide β-hairpin with two facing β-phenylalanine residues. Proc Natl Acad Sci U S A 98 (2001) 3716-3719
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β-hairpins generated from hybrid peptide sequences containing both α- and β-amino acids
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Gopi H.N., Roy R.S., Raghothama S.R., Karle I.L., and Balaram P. β-hairpins generated from hybrid peptide sequences containing both α- and β-amino acids. Helv Chim Acta 85 (2002) 3313-3330
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α, β hybrid peptides: A polypeptide helix with a central segment containing two consecutive β-amino acid residues
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Roy R.S., Karle I.L., Raghothama S., and Balaram P. α, β hybrid peptides: A polypeptide helix with a central segment containing two consecutive β-amino acid residues. Proc Natl Acad Sci U S A 101 (2004) 16478-16482
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A switch between 2-stranded, 3-stranded and 4-stranded coiled coils in Gcn4 leucine-zipper mutants
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Harbury P.B., Zhang T., Kim P.S., and Alber T. A switch between 2-stranded, 3-stranded and 4-stranded coiled coils in Gcn4 leucine-zipper mutants. Science (Washington, DC, US) 262 (1993) 1401-1407
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Helix bundle quaternary structure from α/β-peptide foldamers
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Mixed α/β-peptides designed to mimic natural helical bundles were shown to exhibit some level of quaternary structure via solution characterization and high-resolution structure.
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Horne W.S., Price J.L., Keck J.L., and Gellman S.H. Helix bundle quaternary structure from α/β-peptide foldamers. J Am Chem Soc 129 (2007) 4178-4180. Mixed α/β-peptides designed to mimic natural helical bundles were shown to exhibit some level of quaternary structure via solution characterization and high-resolution structure.
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J Am Chem Soc
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Horne, W.S.1
Price, J.L.2
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A buried polar interaction imparts structural uniqueness in a designed heterodimeric coiled-coil
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Lumb K.J., and Kim P.S. A buried polar interaction imparts structural uniqueness in a designed heterodimeric coiled-coil. Biochemistry 34 (1995) 8642-8648
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Discrete heterogeneous quaternary structure formed by α/β-peptide foldamers and α-peptides
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3-, and cyclic β-amino acids on the ability to of the tetramer to form was explored.
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3-, and cyclic β-amino acids on the ability to of the tetramer to form was explored.
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(2007)
J Am Chem Soc
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Price, J.L.1
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Gellman, S.H.3
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