C-Glucosylation as a tool for the prevention of PAINS-induced membrane dipole potential alterations

Abstract The concept of Pan-Assay Interference Compounds (PAINS) is regarded as a threat to the recognition of the broad bioactivity of natural products. Based on the established relationship between altered membrane dipole potential and transmembrane protein conformation and function, we investigat...

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Autores principales:	Ana Marta de Matos, Maria Teresa Blázquez-Sánchez, Carla Sousa, Maria Conceição Oliveira, Rodrigo F. M. de Almeida, Amélia P. Rauter
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/14eb2adecb684795a97f8a351e9ceaca
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spelling	oai:doaj.org-article:14eb2adecb684795a97f8a351e9ceaca2021-12-02T13:30:50ZC-Glucosylation as a tool for the prevention of PAINS-induced membrane dipole potential alterations10.1038/s41598-021-83032-32045-2322https://doaj.org/article/14eb2adecb684795a97f8a351e9ceaca2021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83032-3https://doaj.org/toc/2045-2322Abstract The concept of Pan-Assay Interference Compounds (PAINS) is regarded as a threat to the recognition of the broad bioactivity of natural products. Based on the established relationship between altered membrane dipole potential and transmembrane protein conformation and function, we investigate here polyphenols' ability to induce changes in cell membrane dipole potential. Ultimately, we are interested in finding a tool to prevent polyphenol PAINS-type behavior and produce compounds less prone to untargeted and promiscuous interactions with the cell membrane. Di-8-ANEPPS fluorescence ratiometric measurements suggest that planar lipophilic polyphenols—phloretin, genistein and resveratrol—act by decreasing membrane dipole potential, especially in cholesterol-rich domains such as lipid rafts, which play a role in important cellular processes. These results provide a mechanism for their labelling as PAINS through their ability to disrupt cell membrane homeostasis. Aiming to explore the role of C-glucosylation in PAINS membrane-interfering behavior, we disclose herein the first synthesis of 4-glucosylresveratrol, starting from 5-hydroxymethylbenzene-1,3-diol, via C-glucosylation, oxidation and Horner-Wadsworth-Emmons olefination, and resynthesize phloretin and genistein C-glucosides. We show that C-glucosylation generates compounds which are no longer able to modify membrane dipole potential. Therefore, it can be devised as a strategy to generate bioactive natural product derivatives that no longer act as membrane dipole potential modifiers. Our results offer a new technology towards rescuing bioactive polyphenols from their PAINS danger label through C–C ligation of sugars.Ana Marta de MatosMaria Teresa Blázquez-SánchezCarla SousaMaria Conceição OliveiraRodrigo F. M. de AlmeidaAmélia P. RauterNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ana Marta de Matos Maria Teresa Blázquez-Sánchez Carla Sousa Maria Conceição Oliveira Rodrigo F. M. de Almeida Amélia P. Rauter C-Glucosylation as a tool for the prevention of PAINS-induced membrane dipole potential alterations
description	Abstract The concept of Pan-Assay Interference Compounds (PAINS) is regarded as a threat to the recognition of the broad bioactivity of natural products. Based on the established relationship between altered membrane dipole potential and transmembrane protein conformation and function, we investigate here polyphenols' ability to induce changes in cell membrane dipole potential. Ultimately, we are interested in finding a tool to prevent polyphenol PAINS-type behavior and produce compounds less prone to untargeted and promiscuous interactions with the cell membrane. Di-8-ANEPPS fluorescence ratiometric measurements suggest that planar lipophilic polyphenols—phloretin, genistein and resveratrol—act by decreasing membrane dipole potential, especially in cholesterol-rich domains such as lipid rafts, which play a role in important cellular processes. These results provide a mechanism for their labelling as PAINS through their ability to disrupt cell membrane homeostasis. Aiming to explore the role of C-glucosylation in PAINS membrane-interfering behavior, we disclose herein the first synthesis of 4-glucosylresveratrol, starting from 5-hydroxymethylbenzene-1,3-diol, via C-glucosylation, oxidation and Horner-Wadsworth-Emmons olefination, and resynthesize phloretin and genistein C-glucosides. We show that C-glucosylation generates compounds which are no longer able to modify membrane dipole potential. Therefore, it can be devised as a strategy to generate bioactive natural product derivatives that no longer act as membrane dipole potential modifiers. Our results offer a new technology towards rescuing bioactive polyphenols from their PAINS danger label through C–C ligation of sugars.
format	article
author	Ana Marta de Matos Maria Teresa Blázquez-Sánchez Carla Sousa Maria Conceição Oliveira Rodrigo F. M. de Almeida Amélia P. Rauter
author_facet	Ana Marta de Matos Maria Teresa Blázquez-Sánchez Carla Sousa Maria Conceição Oliveira Rodrigo F. M. de Almeida Amélia P. Rauter
author_sort	Ana Marta de Matos
title	C-Glucosylation as a tool for the prevention of PAINS-induced membrane dipole potential alterations
title_short	C-Glucosylation as a tool for the prevention of PAINS-induced membrane dipole potential alterations
title_full	C-Glucosylation as a tool for the prevention of PAINS-induced membrane dipole potential alterations
title_fullStr	C-Glucosylation as a tool for the prevention of PAINS-induced membrane dipole potential alterations
title_full_unstemmed	C-Glucosylation as a tool for the prevention of PAINS-induced membrane dipole potential alterations
title_sort	c-glucosylation as a tool for the prevention of pains-induced membrane dipole potential alterations
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/14eb2adecb684795a97f8a351e9ceaca
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C-Glucosylation as a tool for the prevention of PAINS-induced membrane dipole potential alterations

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