Peptoid-Peptide Hybrids That Bind Syk SH2 Domains Involved in Signal Transduction

Ruijtenbeek, Rob; Kruijtzer, John A. W.; Wiel, Wendy van de; Fischer, Marcel J.E.; Flück, Martin; Redegeld, Frank A.; Liskamp, Rob M. J.; Nijkamp, Frans P.

doi:10.1002/1439-7633(20010302)2:3<171::aid-cbic171>3.0.co;2-b

Cited by 46 publications

(35 citation statements)

References 90 publications

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“…The binding affinity of the trans ‐isomer of compound 1 for Syk tSH2 was 10‐fold less than that of native γ‐ITAM ( K D = 65 nM and 5.6 n M , respectively)14, 19. The linker in cis ‐configuration (7.2 Å) was still long enough to bind divalently to both SH2 domains of Syk tSH2, resulting in an affinity ( K D 100% cis was calculated to be 860 n M ) which is significantly better than that of a monovalent interaction ( K D = 27 µ M )14, 22.…”

Section: Resultsmentioning

confidence: 99%

Switching between low and high affinity for the Syk tandem SH2 domain by irradiation of azobenzene containing ITAM peptidomimetics

Kuil¹,

Wandelen²,

Mol³

et al. 2009

Journal of Peptide Science

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Spleen tyrosine kinase (Syk) plays an essential role in IgE receptor signaling (FcepsilonRI), which leads to mast cell degranulation. Divalent binding of the tandem SH2 domain (tSH2) of Syk to the intracellular ITAM motif of FcepsilonRI activates the kinase domain of Syk, and thereby initiates cell degranulation. The inter SH2 domain distance in Syk tSH2 might be important for Syk kinase activation. In this study, photoswitchable ITAM peptidomimetics containing an azobenzene moiety were synthesized. Irradiation of these constructs changes the distance between the two SH2 binding epitopes and therefore, they may be used as photoswitches. The affinity of the cis- and trans-isomer for tSH2 was assayed with SPR. The ITAM peptidomimetic with the smallest linker displayed the largest difference in affinity between the two isomers (at least 100-fold), and the affinity of the cis-isomer was comparable to monovalent binding. The ITAM mimics with larger photoswitchable linkers displayed modest differences. These results indicate that Syk tSH2 is able to adapt the inter SH2 domain distance to ligands larger than native ITAM, but not to smaller ones.

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Section: Resultsmentioning

confidence: 99%

Switching between low and high affinity for the Syk tandem SH2 domain by irradiation of azobenzene containing ITAM peptidomimetics

Kuil¹,

Wandelen²,

Mol³

et al. 2009

Journal of Peptide Science

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show abstract

“…However, because these strategies modify the connectivity, or amino acid identity of the peptide, they can reduce its bioactivity, often necessitating multiple rounds of structure–function studies to restore the activity of the material. 30 Strategies that do not require direct modification of the peptide chemical structure typically involve manipulation of their three-dimensional spatial arrangement via chemical conjugation of the peptide to a higher molecular weight structure. Architectures of this type include peptide–polymer conjugates 31 or systems involving the display of multiple copies of the peptide on a small molecule scaffold.…”

Section: Introductionmentioning

confidence: 99%

Peptides Displayed as High Density Brush Polymers Resist Proteolysis and Retain Bioactivity

et al. 2014

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We describe a strategy for rendering peptides resistant to proteolysis by formulating them as high-density brush polymers. The utility of this approach is demonstrated by polymerizing well-established cell-penetrating peptides (CPPs) and showing that the resulting polymers are not only resistant to proteolysis but also maintain their ability to enter cells. The scope of this design concept is explored by studying the proteolytic resistance of brush polymers composed of peptides that are substrates for either thrombin or a metalloprotease. Finally, we demonstrate that the proteolytic susceptibility of peptide brush polymers can be tuned by adjusting the density of the polymer brush and offer in silico models to rationalize this finding. We contend that this strategy offers a plausible method of preparing peptides for in vivo use, where rapid digestion by proteases has traditionally restricted their utility.

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“…1 and Table 1). 19 Such a set of structurally related peptoid compounds can be used to investigate the extent to which a biologically active peptide can be transformed into a peptoid with retention of activity 19. This is denoted a ‘peptoid scan.’…”

Section: Introductionmentioning

confidence: 99%

Characterization of a phosphorylated peptide and peptoid and peptoid–peptide hybrids by mass spectrometry

Ruijtenbeek

Versluis²,

Heck³

et al. 2001

J. Mass Spectrom.

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Nano-electrospray tandem mass spectrometry (nano-ES-MS/MS) was used to record collision-induced dissociation (CID) spectra of a set of peptoid-peptide hybrids and the complete peptoid derived from the phosphopeptide Ac-pTyr-Glu-Thr-Leu-NH(2) (1). The presence of B and Y''-type fragment ions in the tandem mass spectra of the protonated molecular ions [M + H](+) allowed confirmation of sequence similar to mass spectrometric sequence analysis in peptides. In the isomeric peptoid compounds studied, one or several amino acid residues were replaced by peptoid residues (N-substituted glycine residues), which resulted in characteristic tandem mass spectra with differently increased relative abundances of Y''-and B-type fragment ions. The increment of a particular Y''-ion was directly correlated to the position of a peptoid residue present. In addition to these increased peak intensities, other characteristic peaks were also observed compared with the spectrum of reference peptide 1. When a peptoid phosphotyrosine was incorporated, the presence of this residue was apparent from the occurrence of a relatively intense peak at m/z 187 representing the positively charged side-chain of phosphotyrosine, which was almost absent in the spectrum of the reference peptide 1. Since the threonine side-chain had to be translated into the homo peptoid analog this substitution was apparent from the presence of [M + H](+) and fragment ions 14 mass units higher than observed in the spectrum of the reference phosphopeptide 1. The presence of an NLeu peptoid residue could be confirmed by the specific fragmentation of the immonium ion showing an intense peak in its tandem mass spectrum at m/z 57, which results from the loss of an neutral imine molecule leading to a positively charged [C(4)H(9)](+) ion. By means of these mass spectrometric characteristics, all isomeric peptoid compounds could be distinguished from each other and characterized. The methods used appear to be very useful in future studies of peptoids and peptoid-peptide hybrids.

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Peptoid-Peptide Hybrids That Bind Syk SH2 Domains Involved in Signal Transduction

Cited by 46 publications

References 90 publications

Switching between low and high affinity for the Syk tandem SH2 domain by irradiation of azobenzene containing ITAM peptidomimetics

Switching between low and high affinity for the Syk tandem SH2 domain by irradiation of azobenzene containing ITAM peptidomimetics

Peptides Displayed as High Density Brush Polymers Resist Proteolysis and Retain Bioactivity

Characterization of a phosphorylated peptide and peptoid and peptoid–peptide hybrids by mass spectrometry

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