Sugar-modified G-quadruplexes : effects of LNA-, 2'F-RNA- and 2'F-ANA-guanosine chemistries on G-quadruplex structure and stability

G-quadruplex-forming oligonucleotides containing modified nucleotide chemistries have demonstrated promising pharmaceutical potential. In this work, we systematically investigate the effects of sugar-modified guanosines on the structure and stability of a (4+0) parallel and a (3+1) hybrid G-quadrupl...

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Main Authors: Phan, Anh Tuân, Li, Zhe, Lech, Christopher Jacques
Other Authors: School of Physical and Mathematical Sciences
Format: Article
Language:English
Published: 2014
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Online Access:https://hdl.handle.net/10356/104269
http://hdl.handle.net/10220/19559
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Institution: Nanyang Technological University
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spelling sg-ntu-dr.10356-1042692023-02-28T19:44:56Z Sugar-modified G-quadruplexes : effects of LNA-, 2'F-RNA- and 2'F-ANA-guanosine chemistries on G-quadruplex structure and stability Phan, Anh Tuân Li, Zhe Lech, Christopher Jacques School of Physical and Mathematical Sciences DRNTU::Science::Chemistry G-quadruplex-forming oligonucleotides containing modified nucleotide chemistries have demonstrated promising pharmaceutical potential. In this work, we systematically investigate the effects of sugar-modified guanosines on the structure and stability of a (4+0) parallel and a (3+1) hybrid G-quadruplex using over 60 modified sequences containing a single-position substitution of 2′-O-4′-C-methylene-guanosine (LNAG), 2′-deoxy-2′-fluoro-riboguanosine (FG) or 2′-deoxy-2′-fluoro-arabinoguanosine (FANAG). Our results are summarized in two parts: (I) Generally, LNAG substitutions into ‘anti’ position guanines within a guanine-tetrad lead to a more stable G-quadruplex, while substitutions into ‘syn’ positions disrupt the native G-quadruplex conformation. However, some interesting exceptions to this trend are observed. We discover that a LNAG modification upstream of a short propeller loop hinders G-quadruplex formation. (II) A single substitution of either FG or FANAG into a ‘syn’ position is powerful enough to perturb the (3+1) G-quadruplex. Substitution of either FG or FANAG into any ‘anti’ position is well tolerated in the two G-quadruplex scaffolds. FANAG substitutions to ‘anti’ positions are better tolerated than their FG counterparts. In both scaffolds, FANAG substitutions to the central tetrad layer are observed to be the most stabilizing. The observations reported herein on the effects of LNAG, FG and FANAG modifications on G-quadruplex structure and stability will enable the future design of pharmaceutically relevant oligonucleotides. Published version 2014-06-04T04:42:18Z 2019-12-06T21:29:28Z 2014-06-04T04:42:18Z 2019-12-06T21:29:28Z 2013 2013 Journal Article Li, Z., Lech, C. J., & Phan, A. T. (2014). Sugar-modified G-quadruplexes: effects of LNA-, 2'F-RNA- and 2'F-ANA-guanosine chemistries on G-quadruplex structure and stability. Nucleic Acids Research, 42(6), 4068-4079. 0305-1048 https://hdl.handle.net/10356/104269 http://hdl.handle.net/10220/19559 10.1093/nar/gkt1312 24371274 en Nucleic acids research © The Author(s) 2013. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic DRNTU::Science::Chemistry
spellingShingle DRNTU::Science::Chemistry
Phan, Anh Tuân
Li, Zhe
Lech, Christopher Jacques
Sugar-modified G-quadruplexes : effects of LNA-, 2'F-RNA- and 2'F-ANA-guanosine chemistries on G-quadruplex structure and stability
description G-quadruplex-forming oligonucleotides containing modified nucleotide chemistries have demonstrated promising pharmaceutical potential. In this work, we systematically investigate the effects of sugar-modified guanosines on the structure and stability of a (4+0) parallel and a (3+1) hybrid G-quadruplex using over 60 modified sequences containing a single-position substitution of 2′-O-4′-C-methylene-guanosine (LNAG), 2′-deoxy-2′-fluoro-riboguanosine (FG) or 2′-deoxy-2′-fluoro-arabinoguanosine (FANAG). Our results are summarized in two parts: (I) Generally, LNAG substitutions into ‘anti’ position guanines within a guanine-tetrad lead to a more stable G-quadruplex, while substitutions into ‘syn’ positions disrupt the native G-quadruplex conformation. However, some interesting exceptions to this trend are observed. We discover that a LNAG modification upstream of a short propeller loop hinders G-quadruplex formation. (II) A single substitution of either FG or FANAG into a ‘syn’ position is powerful enough to perturb the (3+1) G-quadruplex. Substitution of either FG or FANAG into any ‘anti’ position is well tolerated in the two G-quadruplex scaffolds. FANAG substitutions to ‘anti’ positions are better tolerated than their FG counterparts. In both scaffolds, FANAG substitutions to the central tetrad layer are observed to be the most stabilizing. The observations reported herein on the effects of LNAG, FG and FANAG modifications on G-quadruplex structure and stability will enable the future design of pharmaceutically relevant oligonucleotides.
author2 School of Physical and Mathematical Sciences
author_facet School of Physical and Mathematical Sciences
Phan, Anh Tuân
Li, Zhe
Lech, Christopher Jacques
format Article
author Phan, Anh Tuân
Li, Zhe
Lech, Christopher Jacques
author_sort Phan, Anh Tuân
title Sugar-modified G-quadruplexes : effects of LNA-, 2'F-RNA- and 2'F-ANA-guanosine chemistries on G-quadruplex structure and stability
title_short Sugar-modified G-quadruplexes : effects of LNA-, 2'F-RNA- and 2'F-ANA-guanosine chemistries on G-quadruplex structure and stability
title_full Sugar-modified G-quadruplexes : effects of LNA-, 2'F-RNA- and 2'F-ANA-guanosine chemistries on G-quadruplex structure and stability
title_fullStr Sugar-modified G-quadruplexes : effects of LNA-, 2'F-RNA- and 2'F-ANA-guanosine chemistries on G-quadruplex structure and stability
title_full_unstemmed Sugar-modified G-quadruplexes : effects of LNA-, 2'F-RNA- and 2'F-ANA-guanosine chemistries on G-quadruplex structure and stability
title_sort sugar-modified g-quadruplexes : effects of lna-, 2'f-rna- and 2'f-ana-guanosine chemistries on g-quadruplex structure and stability
publishDate 2014
url https://hdl.handle.net/10356/104269
http://hdl.handle.net/10220/19559
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