Cargando…

Synthesis of Terminal Ribose Analogues of Adenosine 5′-Diphosphate Ribose as Probes for the Transient Receptor Potential Cation Channel TRPM2

[Image: see text] TRPM2 (transient receptor potential cation channel, subfamily M, member 2) is a nonselective cation channel involved in the response to oxidative stress and in inflammation. Its role in autoimmune and neurodegenerative diseases makes it an attractive pharmacological target. Binding...

Descripción completa

Detalles Bibliográficos
Autores principales: Baszczyňski, Ondřej, Watt, Joanna M., Rozewitz, Monika D., Guse, Andreas H., Fliegert, Ralf, Potter, Barry V. L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2019
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6528165/
https://www.ncbi.nlm.nih.gov/pubmed/30978018
http://dx.doi.org/10.1021/acs.joc.9b00338
_version_ 1783420158272864256
author Baszczyňski, Ondřej
Watt, Joanna M.
Rozewitz, Monika D.
Guse, Andreas H.
Fliegert, Ralf
Potter, Barry V. L.
author_facet Baszczyňski, Ondřej
Watt, Joanna M.
Rozewitz, Monika D.
Guse, Andreas H.
Fliegert, Ralf
Potter, Barry V. L.
author_sort Baszczyňski, Ondřej
collection PubMed
description [Image: see text] TRPM2 (transient receptor potential cation channel, subfamily M, member 2) is a nonselective cation channel involved in the response to oxidative stress and in inflammation. Its role in autoimmune and neurodegenerative diseases makes it an attractive pharmacological target. Binding of the nucleotide adenosine 5′-diphosphate ribose (ADPR) to the cytosolic NUDT9 homology (NUDT9H) domain activates the channel. A detailed understanding of how ADPR interacts with the TRPM2 ligand binding domain is lacking, hampering the rational design of modulators, but the terminal ribose of ADPR is known to be essential for activation. To study its role in more detail, we designed synthetic routes to novel analogues of ADPR and 2′-deoxy-ADPR that were modified only by removal of a single hydroxyl group from the terminal ribose. The ADPR analogues were obtained by coupling nucleoside phosphorimidazolides to deoxysugar phosphates. The corresponding C2″-based analogues proved to be unstable. The C1″- and C3″-ADPR analogues were evaluated electrophysiologically by patch-clamp in TRPM2-expressing HEK293 cells. In addition, a compound with all hydroxyl groups of the terminal ribose blocked as its 1″-β-O-methyl-2″,3″-O-isopropylidene derivative was evaluated. Removal of either C1″ or C3″ hydroxyl groups from ADPR resulted in loss of agonist activity. Both these modifications and blocking all three hydroxyl groups resulted in TRPM2 antagonists. Our results demonstrate the critical role of these hydroxyl groups in channel activation.
format Online
Article
Text
id pubmed-6528165
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher American Chemical Society
record_format MEDLINE/PubMed
spelling pubmed-65281652019-05-22 Synthesis of Terminal Ribose Analogues of Adenosine 5′-Diphosphate Ribose as Probes for the Transient Receptor Potential Cation Channel TRPM2 Baszczyňski, Ondřej Watt, Joanna M. Rozewitz, Monika D. Guse, Andreas H. Fliegert, Ralf Potter, Barry V. L. J Org Chem [Image: see text] TRPM2 (transient receptor potential cation channel, subfamily M, member 2) is a nonselective cation channel involved in the response to oxidative stress and in inflammation. Its role in autoimmune and neurodegenerative diseases makes it an attractive pharmacological target. Binding of the nucleotide adenosine 5′-diphosphate ribose (ADPR) to the cytosolic NUDT9 homology (NUDT9H) domain activates the channel. A detailed understanding of how ADPR interacts with the TRPM2 ligand binding domain is lacking, hampering the rational design of modulators, but the terminal ribose of ADPR is known to be essential for activation. To study its role in more detail, we designed synthetic routes to novel analogues of ADPR and 2′-deoxy-ADPR that were modified only by removal of a single hydroxyl group from the terminal ribose. The ADPR analogues were obtained by coupling nucleoside phosphorimidazolides to deoxysugar phosphates. The corresponding C2″-based analogues proved to be unstable. The C1″- and C3″-ADPR analogues were evaluated electrophysiologically by patch-clamp in TRPM2-expressing HEK293 cells. In addition, a compound with all hydroxyl groups of the terminal ribose blocked as its 1″-β-O-methyl-2″,3″-O-isopropylidene derivative was evaluated. Removal of either C1″ or C3″ hydroxyl groups from ADPR resulted in loss of agonist activity. Both these modifications and blocking all three hydroxyl groups resulted in TRPM2 antagonists. Our results demonstrate the critical role of these hydroxyl groups in channel activation. American Chemical Society 2019-04-12 2019-05-17 /pmc/articles/PMC6528165/ /pubmed/30978018 http://dx.doi.org/10.1021/acs.joc.9b00338 Text en Copyright © 2019 American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
spellingShingle Baszczyňski, Ondřej
Watt, Joanna M.
Rozewitz, Monika D.
Guse, Andreas H.
Fliegert, Ralf
Potter, Barry V. L.
Synthesis of Terminal Ribose Analogues of Adenosine 5′-Diphosphate Ribose as Probes for the Transient Receptor Potential Cation Channel TRPM2
title Synthesis of Terminal Ribose Analogues of Adenosine 5′-Diphosphate Ribose as Probes for the Transient Receptor Potential Cation Channel TRPM2
title_full Synthesis of Terminal Ribose Analogues of Adenosine 5′-Diphosphate Ribose as Probes for the Transient Receptor Potential Cation Channel TRPM2
title_fullStr Synthesis of Terminal Ribose Analogues of Adenosine 5′-Diphosphate Ribose as Probes for the Transient Receptor Potential Cation Channel TRPM2
title_full_unstemmed Synthesis of Terminal Ribose Analogues of Adenosine 5′-Diphosphate Ribose as Probes for the Transient Receptor Potential Cation Channel TRPM2
title_short Synthesis of Terminal Ribose Analogues of Adenosine 5′-Diphosphate Ribose as Probes for the Transient Receptor Potential Cation Channel TRPM2
title_sort synthesis of terminal ribose analogues of adenosine 5′-diphosphate ribose as probes for the transient receptor potential cation channel trpm2
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6528165/
https://www.ncbi.nlm.nih.gov/pubmed/30978018
http://dx.doi.org/10.1021/acs.joc.9b00338
work_keys_str_mv AT baszczynskiondrej synthesisofterminalriboseanaloguesofadenosine5diphosphateriboseasprobesforthetransientreceptorpotentialcationchanneltrpm2
AT wattjoannam synthesisofterminalriboseanaloguesofadenosine5diphosphateriboseasprobesforthetransientreceptorpotentialcationchanneltrpm2
AT rozewitzmonikad synthesisofterminalriboseanaloguesofadenosine5diphosphateriboseasprobesforthetransientreceptorpotentialcationchanneltrpm2
AT guseandreash synthesisofterminalriboseanaloguesofadenosine5diphosphateriboseasprobesforthetransientreceptorpotentialcationchanneltrpm2
AT fliegertralf synthesisofterminalriboseanaloguesofadenosine5diphosphateriboseasprobesforthetransientreceptorpotentialcationchanneltrpm2
AT potterbarryvl synthesisofterminalriboseanaloguesofadenosine5diphosphateriboseasprobesforthetransientreceptorpotentialcationchanneltrpm2