In vivo uptake of antisense oligonucleotide drugs predicted by ab initio quantum mechanical calculations

Abstract Liver and kidney uptake and antisense activity is studied for a series of Locked Nucleic Acid (LNA) oligonucleotides with fully stereo-defined, internucleoside linkages. These stereo-specific phosphorothioates are made with a newly developed synthesis method and are being analyzed both theo...

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Autores principales:	Henrik Frydenlund Hansen, Nanna Albaek, Bo Rode Hansen, Irene Shim, Henrik Bohr, Troels Koch
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c40ca0fae6304ec3a2d19d3ddb08ae86
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spelling	oai:doaj.org-article:c40ca0fae6304ec3a2d19d3ddb08ae862021-12-02T13:18:00ZIn vivo uptake of antisense oligonucleotide drugs predicted by ab initio quantum mechanical calculations10.1038/s41598-021-85453-62045-2322https://doaj.org/article/c40ca0fae6304ec3a2d19d3ddb08ae862021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-85453-6https://doaj.org/toc/2045-2322Abstract Liver and kidney uptake and antisense activity is studied for a series of Locked Nucleic Acid (LNA) oligonucleotides with fully stereo-defined, internucleoside linkages. These stereo-specific phosphorothioates are made with a newly developed synthesis method and are being analyzed both theoretically and experimentally. Their structures are obtained theoretically by using many-body Schrödinger equations applied to a group of 11 stereo-defined LNA antisense oligonucleotides selected for biological experiments. The fully converged electronic structures were obtained from ab initio quantum calculations providing the specific electronic structures. One important result was the observation that the calculated electronic structure, represented by the iso-surface area of the electron density in Å2, correlated linearly with LNA oligonucleotide uptake in the liver and kidney. This study also shows that more complex biological phenomena, such as drug activity, will require more molecular and cellular identifiers than used here before a correlation can be found. Establishing biological correlations between quantum mechanical (QM) calculated structures and antisense oligonucleotides is novel, and this method may constitute new tools in drug discovery.Henrik Frydenlund HansenNanna AlbaekBo Rode HansenIrene ShimHenrik BohrTroels KochNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Henrik Frydenlund Hansen Nanna Albaek Bo Rode Hansen Irene Shim Henrik Bohr Troels Koch In vivo uptake of antisense oligonucleotide drugs predicted by ab initio quantum mechanical calculations
description	Abstract Liver and kidney uptake and antisense activity is studied for a series of Locked Nucleic Acid (LNA) oligonucleotides with fully stereo-defined, internucleoside linkages. These stereo-specific phosphorothioates are made with a newly developed synthesis method and are being analyzed both theoretically and experimentally. Their structures are obtained theoretically by using many-body Schrödinger equations applied to a group of 11 stereo-defined LNA antisense oligonucleotides selected for biological experiments. The fully converged electronic structures were obtained from ab initio quantum calculations providing the specific electronic structures. One important result was the observation that the calculated electronic structure, represented by the iso-surface area of the electron density in Å2, correlated linearly with LNA oligonucleotide uptake in the liver and kidney. This study also shows that more complex biological phenomena, such as drug activity, will require more molecular and cellular identifiers than used here before a correlation can be found. Establishing biological correlations between quantum mechanical (QM) calculated structures and antisense oligonucleotides is novel, and this method may constitute new tools in drug discovery.
format	article
author	Henrik Frydenlund Hansen Nanna Albaek Bo Rode Hansen Irene Shim Henrik Bohr Troels Koch
author_facet	Henrik Frydenlund Hansen Nanna Albaek Bo Rode Hansen Irene Shim Henrik Bohr Troels Koch
author_sort	Henrik Frydenlund Hansen
title	In vivo uptake of antisense oligonucleotide drugs predicted by ab initio quantum mechanical calculations
title_short	In vivo uptake of antisense oligonucleotide drugs predicted by ab initio quantum mechanical calculations
title_full	In vivo uptake of antisense oligonucleotide drugs predicted by ab initio quantum mechanical calculations
title_fullStr	In vivo uptake of antisense oligonucleotide drugs predicted by ab initio quantum mechanical calculations
title_full_unstemmed	In vivo uptake of antisense oligonucleotide drugs predicted by ab initio quantum mechanical calculations
title_sort	in vivo uptake of antisense oligonucleotide drugs predicted by ab initio quantum mechanical calculations
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/c40ca0fae6304ec3a2d19d3ddb08ae86
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In vivo uptake of antisense oligonucleotide drugs predicted by ab initio quantum mechanical calculations

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