A proteomic platform to identify off-target proteins associated with therapeutic modalities that induce protein degradation or gene silencing

Abstract Novel modalities such as PROTAC and RNAi have the ability to inadvertently alter the abundance of endogenous proteins. Currently available in vitro secondary pharmacology assays, which evaluate off-target binding or activity of small molecules, do not fully assess the off-target effects of...

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Autores principales:	Xin Liu, Ye Zhang, Lucas D. Ward, Qinghong Yan, Tanggis Bohnuud, Rocio Hernandez, Socheata Lao, Jing Yuan, Fan Fan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/bceb4a3a9b72451bb8dd1f5b780cc4d7
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spelling	oai:doaj.org-article:bceb4a3a9b72451bb8dd1f5b780cc4d72021-12-02T14:53:35ZA proteomic platform to identify off-target proteins associated with therapeutic modalities that induce protein degradation or gene silencing10.1038/s41598-021-95354-32045-2322https://doaj.org/article/bceb4a3a9b72451bb8dd1f5b780cc4d72021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-95354-3https://doaj.org/toc/2045-2322Abstract Novel modalities such as PROTAC and RNAi have the ability to inadvertently alter the abundance of endogenous proteins. Currently available in vitro secondary pharmacology assays, which evaluate off-target binding or activity of small molecules, do not fully assess the off-target effects of PROTAC and are not applicable to RNAi. To address this gap, we developed a proteomics-based platform to comprehensively evaluate the abundance of off-target proteins. First, we selected off-target proteins using genetics and pharmacology evidence. This process yielded 2813 proteins, which we refer to as the “selected off-target proteome” (SOTP). An iterative algorithm was then used to identify four human cell lines out of 932. The 4 cell lines collectively expressed ~ 80% of the SOTP based on transcriptome data. Second, we used mass spectrometry to quantify the intracellular and extracellular proteins from the selected cell lines. Among over 10,000 quantifiable proteins identified, 1828 were part of the predefined SOTP. The SOTP was designed to be easily modified or expanded, owing to the rational selection process developed and the label free LC–MS/MS approach chosen. This versatility inherent to our platform is essential to design fit-for-purpose studies that can address the dynamic questions faced in investigative toxicology.Xin LiuYe ZhangLucas D. WardQinghong YanTanggis BohnuudRocio HernandezSocheata LaoJing YuanFan FanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Xin Liu Ye Zhang Lucas D. Ward Qinghong Yan Tanggis Bohnuud Rocio Hernandez Socheata Lao Jing Yuan Fan Fan A proteomic platform to identify off-target proteins associated with therapeutic modalities that induce protein degradation or gene silencing
description	Abstract Novel modalities such as PROTAC and RNAi have the ability to inadvertently alter the abundance of endogenous proteins. Currently available in vitro secondary pharmacology assays, which evaluate off-target binding or activity of small molecules, do not fully assess the off-target effects of PROTAC and are not applicable to RNAi. To address this gap, we developed a proteomics-based platform to comprehensively evaluate the abundance of off-target proteins. First, we selected off-target proteins using genetics and pharmacology evidence. This process yielded 2813 proteins, which we refer to as the “selected off-target proteome” (SOTP). An iterative algorithm was then used to identify four human cell lines out of 932. The 4 cell lines collectively expressed ~ 80% of the SOTP based on transcriptome data. Second, we used mass spectrometry to quantify the intracellular and extracellular proteins from the selected cell lines. Among over 10,000 quantifiable proteins identified, 1828 were part of the predefined SOTP. The SOTP was designed to be easily modified or expanded, owing to the rational selection process developed and the label free LC–MS/MS approach chosen. This versatility inherent to our platform is essential to design fit-for-purpose studies that can address the dynamic questions faced in investigative toxicology.
format	article
author	Xin Liu Ye Zhang Lucas D. Ward Qinghong Yan Tanggis Bohnuud Rocio Hernandez Socheata Lao Jing Yuan Fan Fan
author_facet	Xin Liu Ye Zhang Lucas D. Ward Qinghong Yan Tanggis Bohnuud Rocio Hernandez Socheata Lao Jing Yuan Fan Fan
author_sort	Xin Liu
title	A proteomic platform to identify off-target proteins associated with therapeutic modalities that induce protein degradation or gene silencing
title_short	A proteomic platform to identify off-target proteins associated with therapeutic modalities that induce protein degradation or gene silencing
title_full	A proteomic platform to identify off-target proteins associated with therapeutic modalities that induce protein degradation or gene silencing
title_fullStr	A proteomic platform to identify off-target proteins associated with therapeutic modalities that induce protein degradation or gene silencing
title_full_unstemmed	A proteomic platform to identify off-target proteins associated with therapeutic modalities that induce protein degradation or gene silencing
title_sort	proteomic platform to identify off-target proteins associated with therapeutic modalities that induce protein degradation or gene silencing
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/bceb4a3a9b72451bb8dd1f5b780cc4d7
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A proteomic platform to identify off-target proteins associated with therapeutic modalities that induce protein degradation or gene silencing

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