Product Focus: Next Generation Phosphoamino Acid Analogs

Product Focus: Next Generation Phosphoamino Acid Analogs

Published on 29.09.2020

Iris Biotech presents the next-generation of hydrolysis-stable phosphono-analogs of pSer, pThr and pTyr. Fluorination renders the phosphonic acid more acidic and thus an even better mimic of the parent phosphoamino acid.

The preparation of synthetic phosphorylated peptides is of significant interest for research. Among posttranslational modifications that occur in organisms, phosphorylation of serine, threonine and tyrosine is counted among the most important activating ones. Nevertheless, from a chemical point of view, those phosphoesters are highly hydrolysis labile. Iris Biotech’s portfolio already includes phosphono-amino acid derivatives which serve as hydrolysis-stable mimics of pSer, pThr and pTyr, termed Pma (Ser), Pmab (Thr) and Pmp (Tyr).

Phosphoester Serine, Threonine and Tyrosine and its hydrolysis stable phosphono derivatives.

The stability towards hydrolysis that characterizes the phosphono-derivatives has an additional benefit, which is that cellular phosphatases are unable to remove the phosphate group mimic. Consequently, peptides or semi-synthetic proteins that include Pma, Pmab or Pmp are valuable tools for cell-based experiments.
As further innovative improvement, Iris Biotech now expanded the range of hydrolysis-stable mimics. Our new phosphono tyrosine derivative is difluorinated which renders the phosphonic acid more acidic, thus becoming a better mimic of phosphotyrosine than Pmp while keeping the hydrolytic stability. If you are interested in the difluoro phosphono derivatives of serine and threonine, please get in contact – we will provide those based on a custom synthesis inquiry.

Fmoc-protected phosphorylated tyrosine and the hydrolysis stable Pmp and difluoro-Pmp derivative.

All derivatives are suitably protected for use in peptide synthesis by Fmoc strategy. The tert-butyl protecting groups prevent side reactions and can be removed during final deprotection of the peptide.

References:

  • An Intrinsic Hydrophobicity Scale for Amino Acids and Its Application to Fluorinated Compounds; W. Hoffmann, J. Langenhan, S. Huhmann, J. Moschner, R. Chang, M. Accorsi, J. Seo, J. Rademann, G. Meijer, B. Koksch, M. T. Bowers, G. von Helden and K. Pagel; Angew Chem Int Ed Engl 2019; 58: 8216-8220. https://doi.org/10.1002/anie.201813954
  • Phosphatase-Stable Phosphoamino Acid Mimetics That Enhance Binding Affinities with the Polo-Box Domain of Polo-like Kinase 1; D. Hymel and T. R. Burke, Jr.;ChemMedChem2017;12: 202-206.https://doi.org/10.1002/cmdc.201600574
  • Cell-permeable bicyclic peptidyl inhibitors against T-cell protein tyrosine phosphatase from a combinatorial library; H. Liao and D. Pei; Org Biomol Chem 2017; 15: 9595-9598. https://doi.org/10.1039/c7ob02562a
  • Azide-alkyne cycloaddition-mediated cyclization of phosphonopeptides and their evaluation as PTP1B binders and enrichment tools; C. Meyer, B. Hoeger, J. Chatterjee and M. Kohn; Bioorg Med Chem 2015; 23: 2848-53. https://doi.org/10.1016/j.bmc.2015.03.015
  • Development of accessible peptidic tool compounds to study the phosphatase PTP1B in intact cells; C. Meyer, B. Hoeger, K. Temmerman, M. Tatarek-Nossol, V. Pogenberg, J. Bernhagen, M. Wilmanns, A. Kapurniotu and M. Kohn; ACS Chem Biol 2014; 9: 769-76. https://doi.org/10.1021/cb400903u
  • A highly selective and potent PTP-MEG2 inhibitor with therapeutic potential for type 2 diabetes; S. Zhang, S. Liu, R. Tao, D. Wei, L. Chen, W. Shen, Z. H. Yu, L. Wang, D. R. Jones, X. C. Dong and Z. Y. Zhang; J Am Chem Soc 2012; 134: 18116-24. https://doi.org/10.1021/ja308212y
  • Acquisition of a potent and selective TC-PTP inhibitor via a stepwise fluorophore-tagged combinatorial synthesis and screening strategy; S. Zhang, L. Chen, Y. Luo, A. Gunawan, D. S. Lawrence and Z. Y. Zhang; J Am Chem Soc 2009; 131: 13072-9. https://doi.org/10.1021/ja903733z
  • Cellular effects of small molecule PTP1B inhibitors on insulin signaling; L. Xie, S. Y. Lee, J. N. Andersen, S. Waters, K. Shen, X. L. Guo, N. P. Moller, J. M. Olefsky, D. S. Lawrence and Z. Y. Zhang; Biochemistry 2003; 42: 12792-804. https://doi.org/10.1021/bi035238p
  • Acquisition of a specific and potent PTP1B inhibitor from a novel combinatorial library and screening procedure; K. Shen, Y. F. Keng, L. Wu, X. L. Guo, D. S. Lawrence and Z. Y. Zhang; J Biol Chem 2001; 276: 47311-9. https://doi.org/10.1074/jbc.M106568200
  • Why is phosphonodifluoromethyl phenylalanine a more potent inhibitory moiety than phosphonomethyl phenylalanine toward protein-tyrosine phosphatases?; L. Chen, L. Wu, A. Otaka, M. S. Smyth, P. P. Roller, T. R. Burke, Jr., J. den Hertog and Z. Y. Zhang; Biochemical and biophysical research communications 1995; 216: 976-84. https://doi.org/10.1006/bbrc.1995.2716
  • Potent inhibition of insulin receptor dephosphorylation by a hexamer peptide containing the phosphotyrosyl mimetic F2Pmp; T. R. Burke, Jr., H. K. Kole and P. P. Roller; Biochemical and biophysical research communications 1994; 204: 129-34. https://doi.org/10.1006/bbrc.1994.2435


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