dc.contributor.authorPatil, Kiran M.
dc.contributor.authorToh, Desiree-Faye Kaixin
dc.contributor.authorYuan, Zhen
dc.contributor.authorMeng, Zhenyu
dc.contributor.authorShu, Zhiyu
dc.contributor.authorZhang, Haiping
dc.contributor.authorOng, Alan Ann Lerk
dc.contributor.authorKrishna, Manchugondanahalli Shivakumar
dc.contributor.authorLu, Lanyuan
dc.contributor.authorLu, Yunpeng
dc.contributor.authorChen, Gang
dc.identifier.citationPatil, K. M., Toh, D.-F. K., Yuan, Z., Meng, Z., Shu, Z., Zhang, H., . . . Chen, G. (2018). Incorporating uracil and 5-halouracils into short peptide nucleic acids for enhanced recognition of A–U pairs in dsRNAs. Nucleic Acids Research, 46(15), 7506-7521. doi:10.1093/nar/gky631en_US
dc.description.abstractDouble-stranded RNA (dsRNA) structures form triplexes and RNA-protein complexes through binding to single-stranded RNA (ssRNA) regions and proteins, respectively, for diverse biological functions. Hence, targeting dsRNAs through major-groove triplex formation is a promising strategy for the development of chemical probes and potential therapeutics. Short (e.g., 6–10 mer) chemically-modified Peptide Nucleic Acids (PNAs) have been developed that bind to dsRNAs sequence specifically at physiological conditions. For example, a PNA incorporating a modified base thio-pseudoisocytosine (L) has an enhanced recognition of a G–C pair in an RNA duplex through major-groove L·G–C base triple formation at physiological pH, with reduced pH dependence as observed for C+·G–C base triple formation. Currently, an unmodified T base is often incorporated into PNAs to recognize a Watson–Crick A–U pair through major-groove T·A–U base triple formation. A substitution of the 5-methyl group in T by hydrogen and halogen atoms (F, Cl, Br, and I) causes a decrease of the pKa of N3 nitrogen atom, which may result in improved hydrogen bonding in addition to enhanced base stacking interactions. Here, we synthesized a series of PNAs incorporating uracil and halouracils, followed by binding studies by non-denaturing polyacrylamide gel electrophoresis, circular dichroism, and thermal melting. Our results suggest that replacing T with uracil and halouracils may enhance the recognition of an A–U pair by PNA·RNA2 triplex formation in a sequence-dependent manner, underscoring the importance of local stacking interactions. Incorporating bromouracils and chlorouracils into a PNA results in a significantly reduced pH dependence of triplex formation even for PNAs containing C bases, likely due to an upshift of the apparent pKa of N3 atoms of C bases. Thus, halogenation and other chemical modifications may be utilized to enhance hydrogen bonding of the adjacent base triples and thus triplex formation. Furthermore, our experimental and computational modelling data suggest that PNA·RNA2 triplexes may be stabilized by incorporating a BrUL step but not an LBrU step, in dsRNA-binding PNAs.en_US
dc.description.sponsorshipMOE (Min. of Education, S’pore)en_US
dc.format.extent16 p.en_US
dc.relation.ispartofseriesNucleic Acids Researchen_US
dc.rights© 2018 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comen_US
dc.subjectDouble-stranded RNAen_US
dc.subjectEnhanced Recognitionen_US
dc.subjectDRNTU::Science::Biological sciencesen_US
dc.titleIncorporating uracil and 5-halouracils into short peptide nucleic acids for enhanced recognition of A–U pairs in dsRNAsen_US
dc.typeJournal Article
dc.contributor.schoolSchool of Biological Sciencesen_US
dc.contributor.schoolSchool of Physical and Mathematical Sciencesen_US
dc.description.versionPublished versionen_US

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