Cargando…

Synthesis of Highly Selective Submicromolar Microcystin‐Based Inhibitors of Protein Phosphatase (PP)2A over PP1

Research and therapeutic targeting of the phosphoserine/threonine phosphatases PP1 and PP2A is hindered by the lack of selective inhibitors. The microcystin (MC) natural toxins target both phosphatases with equal potency, and their complex synthesis has complicated structure–activity relationship st...

Descripción completa

Detalles Bibliográficos
Autores principales: Fontanillo, Miriam, Zemskov, Ivan, Häfner, Maximilian, Uhrig, Ulrike, Salvi, Francesca, Simon, Bernd, Wittmann, Valentin, Köhn, Maja
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5113787/
https://www.ncbi.nlm.nih.gov/pubmed/27723199
http://dx.doi.org/10.1002/anie.201606449
_version_ 1782468245211578368
author Fontanillo, Miriam
Zemskov, Ivan
Häfner, Maximilian
Uhrig, Ulrike
Salvi, Francesca
Simon, Bernd
Wittmann, Valentin
Köhn, Maja
author_facet Fontanillo, Miriam
Zemskov, Ivan
Häfner, Maximilian
Uhrig, Ulrike
Salvi, Francesca
Simon, Bernd
Wittmann, Valentin
Köhn, Maja
author_sort Fontanillo, Miriam
collection PubMed
description Research and therapeutic targeting of the phosphoserine/threonine phosphatases PP1 and PP2A is hindered by the lack of selective inhibitors. The microcystin (MC) natural toxins target both phosphatases with equal potency, and their complex synthesis has complicated structure–activity relationship studies in the past. We report herein the synthesis and biochemical evaluation of 11 MC analogues, which was accomplished through an efficient strategy combining solid‐ and solution‐phase approaches. Our approach led to the first MC analogue with submicromolar inhibitory potency that is strongly selective for PP2A over PP1 and does not require the complex lipophilic Adda group. Through mutational and structural analyses, we identified a new key element for binding, as well as reasons for the selectivity. This work gives unprecedented insight into how selectivity between these phosphatases can be achieved with MC analogues.
format Online
Article
Text
id pubmed-5113787
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-51137872016-11-30 Synthesis of Highly Selective Submicromolar Microcystin‐Based Inhibitors of Protein Phosphatase (PP)2A over PP1 Fontanillo, Miriam Zemskov, Ivan Häfner, Maximilian Uhrig, Ulrike Salvi, Francesca Simon, Bernd Wittmann, Valentin Köhn, Maja Angew Chem Int Ed Engl Communications Research and therapeutic targeting of the phosphoserine/threonine phosphatases PP1 and PP2A is hindered by the lack of selective inhibitors. The microcystin (MC) natural toxins target both phosphatases with equal potency, and their complex synthesis has complicated structure–activity relationship studies in the past. We report herein the synthesis and biochemical evaluation of 11 MC analogues, which was accomplished through an efficient strategy combining solid‐ and solution‐phase approaches. Our approach led to the first MC analogue with submicromolar inhibitory potency that is strongly selective for PP2A over PP1 and does not require the complex lipophilic Adda group. Through mutational and structural analyses, we identified a new key element for binding, as well as reasons for the selectivity. This work gives unprecedented insight into how selectivity between these phosphatases can be achieved with MC analogues. John Wiley and Sons Inc. 2016-10-10 2016-11-02 /pmc/articles/PMC5113787/ /pubmed/27723199 http://dx.doi.org/10.1002/anie.201606449 Text en © 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs (http://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Communications
Fontanillo, Miriam
Zemskov, Ivan
Häfner, Maximilian
Uhrig, Ulrike
Salvi, Francesca
Simon, Bernd
Wittmann, Valentin
Köhn, Maja
Synthesis of Highly Selective Submicromolar Microcystin‐Based Inhibitors of Protein Phosphatase (PP)2A over PP1
title Synthesis of Highly Selective Submicromolar Microcystin‐Based Inhibitors of Protein Phosphatase (PP)2A over PP1
title_full Synthesis of Highly Selective Submicromolar Microcystin‐Based Inhibitors of Protein Phosphatase (PP)2A over PP1
title_fullStr Synthesis of Highly Selective Submicromolar Microcystin‐Based Inhibitors of Protein Phosphatase (PP)2A over PP1
title_full_unstemmed Synthesis of Highly Selective Submicromolar Microcystin‐Based Inhibitors of Protein Phosphatase (PP)2A over PP1
title_short Synthesis of Highly Selective Submicromolar Microcystin‐Based Inhibitors of Protein Phosphatase (PP)2A over PP1
title_sort synthesis of highly selective submicromolar microcystin‐based inhibitors of protein phosphatase (pp)2a over pp1
topic Communications
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5113787/
https://www.ncbi.nlm.nih.gov/pubmed/27723199
http://dx.doi.org/10.1002/anie.201606449
work_keys_str_mv AT fontanillomiriam synthesisofhighlyselectivesubmicromolarmicrocystinbasedinhibitorsofproteinphosphatasepp2aoverpp1
AT zemskovivan synthesisofhighlyselectivesubmicromolarmicrocystinbasedinhibitorsofproteinphosphatasepp2aoverpp1
AT hafnermaximilian synthesisofhighlyselectivesubmicromolarmicrocystinbasedinhibitorsofproteinphosphatasepp2aoverpp1
AT uhrigulrike synthesisofhighlyselectivesubmicromolarmicrocystinbasedinhibitorsofproteinphosphatasepp2aoverpp1
AT salvifrancesca synthesisofhighlyselectivesubmicromolarmicrocystinbasedinhibitorsofproteinphosphatasepp2aoverpp1
AT simonbernd synthesisofhighlyselectivesubmicromolarmicrocystinbasedinhibitorsofproteinphosphatasepp2aoverpp1
AT wittmannvalentin synthesisofhighlyselectivesubmicromolarmicrocystinbasedinhibitorsofproteinphosphatasepp2aoverpp1
AT kohnmaja synthesisofhighlyselectivesubmicromolarmicrocystinbasedinhibitorsofproteinphosphatasepp2aoverpp1