Aptamer-enabled uptake of small molecule ligands

Abstract The relative ease of isolating aptamers with high specificity for target molecules suggests that molecular recognition may be common in the folds of natural RNAs. We show here that, when expressed in cells, aptamers can increase the intracellular concentrations of their small molecule ligan...

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Autores principales:	Supipi Liyamali Auwardt, Yeon-Jung Seo, Muslum Ilgu, Judhajeet Ray, Robert R. Feldges, Shambhavi Shubham, Lee Bendickson, Howard A. Levine, Marit Nilsen-Hamilton
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Small Molecule Ligands Riboswitches Last Universal Common Ancestor (LUCA) DRAG IN Free Intracellular Concentration Medicine R Science Q
Acceso en línea:	https://doaj.org/article/dfe7e4de04d0438488801b4f79c94ba4
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spelling	oai:doaj.org-article:dfe7e4de04d0438488801b4f79c94ba42021-12-02T15:08:38ZAptamer-enabled uptake of small molecule ligands10.1038/s41598-018-33887-w2045-2322https://doaj.org/article/dfe7e4de04d0438488801b4f79c94ba42018-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-33887-whttps://doaj.org/toc/2045-2322Abstract The relative ease of isolating aptamers with high specificity for target molecules suggests that molecular recognition may be common in the folds of natural RNAs. We show here that, when expressed in cells, aptamers can increase the intracellular concentrations of their small molecule ligands. We have named these aptamers as DRAGINs (Drug Binding Aptamers for Growing Intracellular Numbers). The DRAGIN property, assessed here by the ability to enhance the toxicity of their ligands, was found for some, but not all, aminoglycoside aptamers. One aptamer protected cells against killing by its ligand. Another aptamer promoted killing as a singlemer and protected against killing as a tandemer. Based on a mathematical model, cell protection vs. killing is proposed as governed by aptamer affinity and access to the inner surface of the cell membrane, with the latter being a critical determinant. With RNA molecules proposed as the earliest functional polymers to drive the evolution of life, we suggest that RNA aptamer-like structures present in primitive cells might have selectively concentrated precursors for polymer synthesis. Riboswitches may be the evolved forms of these ancient aptamer-like “nutrient procurers”. Aptamers with DRAGIN capability in the modern world could be applied for imaging cells, in synthetic cell constructs, or to draw drugs into cells to make “undruggable” targets accessible to small molecule inhibitors.Supipi Liyamali AuwardtYeon-Jung SeoMuslum IlguJudhajeet RayRobert R. FeldgesShambhavi ShubhamLee BendicksonHoward A. LevineMarit Nilsen-HamiltonNature PortfolioarticleSmall Molecule LigandsRiboswitchesLast Universal Common Ancestor (LUCA)DRAG INFree Intracellular ConcentrationMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-10 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Small Molecule Ligands Riboswitches Last Universal Common Ancestor (LUCA) DRAG IN Free Intracellular Concentration Medicine R Science Q
spellingShingle	Small Molecule Ligands Riboswitches Last Universal Common Ancestor (LUCA) DRAG IN Free Intracellular Concentration Medicine R Science Q Supipi Liyamali Auwardt Yeon-Jung Seo Muslum Ilgu Judhajeet Ray Robert R. Feldges Shambhavi Shubham Lee Bendickson Howard A. Levine Marit Nilsen-Hamilton Aptamer-enabled uptake of small molecule ligands
description	Abstract The relative ease of isolating aptamers with high specificity for target molecules suggests that molecular recognition may be common in the folds of natural RNAs. We show here that, when expressed in cells, aptamers can increase the intracellular concentrations of their small molecule ligands. We have named these aptamers as DRAGINs (Drug Binding Aptamers for Growing Intracellular Numbers). The DRAGIN property, assessed here by the ability to enhance the toxicity of their ligands, was found for some, but not all, aminoglycoside aptamers. One aptamer protected cells against killing by its ligand. Another aptamer promoted killing as a singlemer and protected against killing as a tandemer. Based on a mathematical model, cell protection vs. killing is proposed as governed by aptamer affinity and access to the inner surface of the cell membrane, with the latter being a critical determinant. With RNA molecules proposed as the earliest functional polymers to drive the evolution of life, we suggest that RNA aptamer-like structures present in primitive cells might have selectively concentrated precursors for polymer synthesis. Riboswitches may be the evolved forms of these ancient aptamer-like “nutrient procurers”. Aptamers with DRAGIN capability in the modern world could be applied for imaging cells, in synthetic cell constructs, or to draw drugs into cells to make “undruggable” targets accessible to small molecule inhibitors.
format	article
author	Supipi Liyamali Auwardt Yeon-Jung Seo Muslum Ilgu Judhajeet Ray Robert R. Feldges Shambhavi Shubham Lee Bendickson Howard A. Levine Marit Nilsen-Hamilton
author_facet	Supipi Liyamali Auwardt Yeon-Jung Seo Muslum Ilgu Judhajeet Ray Robert R. Feldges Shambhavi Shubham Lee Bendickson Howard A. Levine Marit Nilsen-Hamilton
author_sort	Supipi Liyamali Auwardt
title	Aptamer-enabled uptake of small molecule ligands
title_short	Aptamer-enabled uptake of small molecule ligands
title_full	Aptamer-enabled uptake of small molecule ligands
title_fullStr	Aptamer-enabled uptake of small molecule ligands
title_full_unstemmed	Aptamer-enabled uptake of small molecule ligands
title_sort	aptamer-enabled uptake of small molecule ligands
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/dfe7e4de04d0438488801b4f79c94ba4
work_keys_str_mv	AT supipiliyamaliauwardt aptamerenableduptakeofsmallmoleculeligands AT yeonjungseo aptamerenableduptakeofsmallmoleculeligands AT muslumilgu aptamerenableduptakeofsmallmoleculeligands AT judhajeetray aptamerenableduptakeofsmallmoleculeligands AT robertrfeldges aptamerenableduptakeofsmallmoleculeligands AT shambhavishubham aptamerenableduptakeofsmallmoleculeligands AT leebendickson aptamerenableduptakeofsmallmoleculeligands AT howardalevine aptamerenableduptakeofsmallmoleculeligands AT maritnilsenhamilton aptamerenableduptakeofsmallmoleculeligands
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Aptamer-enabled uptake of small molecule ligands

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