Synthesis of linear and cyclic phosphopeptides as ligands for the N-terminal SH2-domain of protein tyrosine phosphatase SHP-1. |
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Authors: | Diana Imhof Doreen Nothmann Mohammad Safa Zoda Kornelia Hampel Jenny Wegert Frank D Bhmer Siegmund Reissmann |
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Institution: | Institute of Biochemistry and Biophysics, Biological-Pharmaceutical Faculty, Friedrich-Schiller-University, Philosophenweg 12, D-07743 Jena, Germany. b4imdi@rz.uni-jena.de |
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Abstract: | Linear and cyclic phosphopeptides related to the pY2267 binding site of the epithelial receptor tyrosine kinase Ros have been synthesized as ligands for the amino-terminal SH2 (src homology) domain of protein tyrosine phosphatase SHP-1. The synthesis was accomplished by Fmoc-based solid-phase methodology using side-chain unprotected phosphotyrosine for the linear and mono-benzyl protected phosphotyrosine for the cyclic peptides. According to molecular modelling, the incorporation of a glycine residue between Lys (position pY-1 relative to phosphotyrosine) and Asp or Glu (position pY+2) was recommended for the cyclic candidates. The preparation of these peptides was successfully performed by the incorporation of a Fmoc-Xxx(Gly-OAll)-OH (Xxx = Asp, Glu) dipeptide building block that was prepared in solution prior to SPPS. The cyclization was achieved with PyBOP following Alloc/OAll-deprotection. This study demonstrates the usefulness of allyl-type protecting groups for the generation of side-chain cyclized phosphopeptides. Alloc/OAll-deprotection and cyclization are compatible with phosphorylated tyrosine. |
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Keywords: | SHP‐1 SH2 domain ligands phosphopeptide synthesis cyclic peptides |
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