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Pentafluorophosphato‐Phenylalanines: Amphiphilic Phosphotyrosine Mimetics Displaying Fluorine‐Specific Protein Interactions

Phosphotyrosine residues are essential functional switches in health and disease. Thus, phosphotyrosine biomimetics are crucial for the development of chemical tools and drug molecules. We report here the discovery and investigation of pentafluorophosphato amino acids as novel phosphotyrosine biomim...

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Autores principales: Accorsi, Matteo, Tiemann, Markus, Wehrhan, Leon, Finn, Lauren M., Cruz, Ruben, Rautenberg, Max, Emmerling, Franziska, Heberle, Joachim, Keller, Bettina G., Rademann, Jörg
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9323422/
https://www.ncbi.nlm.nih.gov/pubmed/35303375
http://dx.doi.org/10.1002/anie.202203579
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author Accorsi, Matteo
Tiemann, Markus
Wehrhan, Leon
Finn, Lauren M.
Cruz, Ruben
Rautenberg, Max
Emmerling, Franziska
Heberle, Joachim
Keller, Bettina G.
Rademann, Jörg
author_facet Accorsi, Matteo
Tiemann, Markus
Wehrhan, Leon
Finn, Lauren M.
Cruz, Ruben
Rautenberg, Max
Emmerling, Franziska
Heberle, Joachim
Keller, Bettina G.
Rademann, Jörg
author_sort Accorsi, Matteo
collection PubMed
description Phosphotyrosine residues are essential functional switches in health and disease. Thus, phosphotyrosine biomimetics are crucial for the development of chemical tools and drug molecules. We report here the discovery and investigation of pentafluorophosphato amino acids as novel phosphotyrosine biomimetics. A mild acidic pentafluorination protocol was developed and two PF(5)‐amino acids were prepared and employed in peptide synthesis. Their structures, reactivities, and fluorine‐specific interactions were studied by NMR and IR spectroscopy, X‐ray diffraction, and in bioactivity assays. The mono‐anionic PF(5) motif displayed an amphiphilic character binding to hydrophobic surfaces, to water molecules, and to protein‐binding sites, exploiting charge and H−F‐bonding interactions. The novel motifs bind 25‐ to 30‐fold stronger to the phosphotyrosine binding site of the protein tyrosine phosphatase PTP1B than the best current biomimetics, as rationalized by computational methods, including molecular dynamics simulations.
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spelling pubmed-93234222022-07-30 Pentafluorophosphato‐Phenylalanines: Amphiphilic Phosphotyrosine Mimetics Displaying Fluorine‐Specific Protein Interactions Accorsi, Matteo Tiemann, Markus Wehrhan, Leon Finn, Lauren M. Cruz, Ruben Rautenberg, Max Emmerling, Franziska Heberle, Joachim Keller, Bettina G. Rademann, Jörg Angew Chem Int Ed Engl Communications Phosphotyrosine residues are essential functional switches in health and disease. Thus, phosphotyrosine biomimetics are crucial for the development of chemical tools and drug molecules. We report here the discovery and investigation of pentafluorophosphato amino acids as novel phosphotyrosine biomimetics. A mild acidic pentafluorination protocol was developed and two PF(5)‐amino acids were prepared and employed in peptide synthesis. Their structures, reactivities, and fluorine‐specific interactions were studied by NMR and IR spectroscopy, X‐ray diffraction, and in bioactivity assays. The mono‐anionic PF(5) motif displayed an amphiphilic character binding to hydrophobic surfaces, to water molecules, and to protein‐binding sites, exploiting charge and H−F‐bonding interactions. The novel motifs bind 25‐ to 30‐fold stronger to the phosphotyrosine binding site of the protein tyrosine phosphatase PTP1B than the best current biomimetics, as rationalized by computational methods, including molecular dynamics simulations. John Wiley and Sons Inc. 2022-04-25 2022-06-20 /pmc/articles/PMC9323422/ /pubmed/35303375 http://dx.doi.org/10.1002/anie.202203579 Text en © 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Communications
Accorsi, Matteo
Tiemann, Markus
Wehrhan, Leon
Finn, Lauren M.
Cruz, Ruben
Rautenberg, Max
Emmerling, Franziska
Heberle, Joachim
Keller, Bettina G.
Rademann, Jörg
Pentafluorophosphato‐Phenylalanines: Amphiphilic Phosphotyrosine Mimetics Displaying Fluorine‐Specific Protein Interactions
title Pentafluorophosphato‐Phenylalanines: Amphiphilic Phosphotyrosine Mimetics Displaying Fluorine‐Specific Protein Interactions
title_full Pentafluorophosphato‐Phenylalanines: Amphiphilic Phosphotyrosine Mimetics Displaying Fluorine‐Specific Protein Interactions
title_fullStr Pentafluorophosphato‐Phenylalanines: Amphiphilic Phosphotyrosine Mimetics Displaying Fluorine‐Specific Protein Interactions
title_full_unstemmed Pentafluorophosphato‐Phenylalanines: Amphiphilic Phosphotyrosine Mimetics Displaying Fluorine‐Specific Protein Interactions
title_short Pentafluorophosphato‐Phenylalanines: Amphiphilic Phosphotyrosine Mimetics Displaying Fluorine‐Specific Protein Interactions
title_sort pentafluorophosphato‐phenylalanines: amphiphilic phosphotyrosine mimetics displaying fluorine‐specific protein interactions
topic Communications
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9323422/
https://www.ncbi.nlm.nih.gov/pubmed/35303375
http://dx.doi.org/10.1002/anie.202203579
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