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dc.contributor.authorYamada, Ken
dc.contributor.authorHildebrand, Samuel
dc.contributor.authorDavis, Sarah M
dc.contributor.authorMiller, Rachael
dc.contributor.authorConroy, Faith
dc.contributor.authorSapp, Ellen
dc.contributor.authorCaiazzi, Jillian
dc.contributor.authorAlterman, Julia F
dc.contributor.authorRoux, Loic
dc.contributor.authorEcheverria, Dimas
dc.contributor.authorHassler, Matthew R
dc.contributor.authorPfister, Edith L
dc.contributor.authorDiFiglia, Marian
dc.contributor.authorAronin, Neil
dc.contributor.authorKhvorova, Anastasia
dc.date.accessioned2023-04-25T18:05:14Z
dc.date.available2023-04-25T18:05:14Z
dc.date.issued2021-11-25
dc.identifier.citationYamada K, Hildebrand S, Davis SM, Miller R, Conroy F, Sapp E, Caiazzi J, Alterman JF, Roux L, Echeverria D, Hassler MR, Pfister EL, DiFiglia M, Aronin N, Khvorova A. Structurally constrained phosphonate internucleotide linkage impacts oligonucleotide-enzyme interaction, and modulates siRNA activity and allele specificity. Nucleic Acids Res. 2021 Dec 2;49(21):12069-12088. doi: 10.1093/nar/gkab1126. PMID: 34850120; PMCID: PMC8643693.en_US
dc.identifier.eissn1362-4962
dc.identifier.doi10.1093/nar/gkab1126en_US
dc.identifier.pmid34850120
dc.identifier.urihttp://hdl.handle.net/20.500.14038/51989
dc.description.abstractOligonucleotides is an emerging class of chemically-distinct therapeutic modalities, where extensive chemical modifications are fundamental for their clinical applications. Inter-nucleotide backbones are critical to the behaviour of therapeutic oligonucleotides, but clinically explored backbone analogues are, effectively, limited to phosphorothioates. Here, we describe the synthesis and bio-functional characterization of an internucleotide (E)-vinylphosphonate (iE-VP) backbone, where bridging oxygen is substituted with carbon in a locked stereo-conformation. After optimizing synthetic pathways for iE-VP-linked dimer phosphoramidites in different sugar contexts, we systematically evaluated the impact of the iE-VP backbone on oligonucleotide interactions with a variety of cellular proteins. Furthermore, we systematically evaluated the impact of iE-VP on RNA-Induced Silencing Complex (RISC) activity, where backbone stereo-constraining has profound position-specific effects. Using Huntingtin (HTT) gene causative of Huntington's disease as an example, iE-VP at position 6 significantly enhanced the single mismatch discrimination ability of the RISC without negative impact on silencing of targeting wild type htt gene. These findings suggest that the iE-VP backbone can be used to modulate the activity and specificity of RISC. Our study provides (i) a new chemical tool to alter oligonucleotide-enzyme interactions and metabolic stability, (ii) insight into RISC dynamics and (iii) a new strategy for highly selective SNP-discriminating siRNAs.en_US
dc.language.isoenen_US
dc.relation.ispartofNucleic Acids Researchen_US
dc.relation.urlhttps://doi.org/10.1093/nar/gkab1126en_US
dc.rights© The Author(s) 2021. 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 License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.; Attribution 4.0 Internationalen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.titleStructurally constrained phosphonate internucleotide linkage impacts oligonucleotide-enzyme interaction, and modulates siRNA activity and allele specificityen_US
dc.typeJournal Articleen_US
dc.source.journaltitleNucleic acids research
dc.source.volume49
dc.source.issue21
dc.source.beginpage12069
dc.source.endpage12088
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryEngland
dc.identifier.journalNucleic acids research
refterms.dateFOA2023-04-25T18:05:15Z
dc.contributor.departmentMedicineen_US
dc.contributor.departmentMorningside Graduate School of Biomedical Sciencesen_US
dc.contributor.departmentProgram in Molecular Medicineen_US
dc.contributor.departmentRNA Therapeutics Instituteen_US
dc.contributor.studentSamuel Hildebrand
dc.contributor.studentSarah M. Davis
dc.contributor.studentRachael Miller
dc.description.thesisprogramInterdisciplinary Graduate Program


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© The Author(s) 2021. 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 License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.; Attribution 4.0 International
Except where otherwise noted, this item's license is described as © The Author(s) 2021. 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 License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.; Attribution 4.0 International