{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T03:04:37Z","timestamp":1791428677619,"version":"4.3.3"},"reference-count":69,"publisher":"Oxford University Press (OUP)","issue":"21","license":[{"start":{"date-parts":[[2021,11,25]],"date-time":"2021-11-25T00:00:00Z","timestamp":1637798400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"NINDS","doi-asserted-by":"publisher","award":["R01 NS104022"],"award-info":[{"award-number":["R01 NS104022"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"name":"S10","award":["OD020012"],"award-info":[{"award-number":["OD020012"]}]},{"name":"MIRA","award":["R35 GM131839"],"award-info":[{"award-number":["R35 GM131839"]}]},{"name":"NIH CREATE","award":["U01 NS114098"],"award-info":[{"award-number":["U01 NS114098"]}]},{"DOI":"10.13039\/100005725","name":"CHDI Foundation","doi-asserted-by":"publisher","award":["RecID A-5038"],"award-info":[{"award-number":["RecID A-5038"]}],"id":[{"id":"10.13039\/100005725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,12,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Oligonucleotides 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\u00a0and (iii) a new strategy for highly selective SNP-discriminating siRNAs.<\/jats:p>","DOI":"10.1093\/nar\/gkab1126","type":"journal-article","created":{"date-parts":[[2021,10,27]],"date-time":"2021-10-27T19:13:38Z","timestamp":1635362018000},"page":"12069-12088","source":"Crossref","is-referenced-by-count":21,"title":["Structurally constrained phosphonate internucleotide linkage impacts oligonucleotide-enzyme interaction, and modulates siRNA activity and allele specificity"],"prefix":"10.1093","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5714-8298","authenticated-orcid":false,"given":"Ken","family":"Yamada","sequence":"first","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6633-3495","authenticated-orcid":false,"given":"Samuel","family":"Hildebrand","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5758-1924","authenticated-orcid":false,"given":"Sarah M","family":"Davis","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael","family":"Miller","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA"},{"name":"Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9934-7308","authenticated-orcid":false,"given":"Faith","family":"Conroy","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA"},{"name":"Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Sapp","sequence":"additional","affiliation":[{"name":"Department of Neurology, Harvard Medical School and MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7077-2116","authenticated-orcid":false,"given":"Jillian","family":"Caiazzi","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6195-0857","authenticated-orcid":false,"given":"Julia F","family":"Alterman","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6099-0427","authenticated-orcid":false,"given":"Loic","family":"Roux","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1040-0855","authenticated-orcid":false,"given":"Dimas","family":"Echeverria","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7897-6503","authenticated-orcid":false,"given":"Matthew R","family":"Hassler","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0345-7773","authenticated-orcid":false,"given":"Edith L","family":"Pfister","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marian","family":"DiFiglia","sequence":"additional","affiliation":[{"name":"Department of Neurology, Harvard Medical School and MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil","family":"Aronin","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA"},{"name":"Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6928-8071","authenticated-orcid":false,"given":"Anastasia","family":"Khvorova","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA"},{"name":"Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,11,25]]},"reference":[{"key":"2021120508571793000_B1","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/nbt.3765","article-title":"The chemical evolution of oligonucleotide therapies of clinical utility","volume":"35","author":"Khvorova","year":"2017","journal-title":"Nat. Biotechnol."},{"key":"2021120508571793000_B2","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1016\/j.cmet.2018.03.004","article-title":"RNA targeted therapeutics","volume":"27","author":"Crooke","year":"2018","journal-title":"Cell Metab."},{"key":"2021120508571793000_B3","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1056\/NEJMra1705346","article-title":"Treating disease at the RNA level with oligonucleotides","volume":"380","author":"Levin","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"2021120508571793000_B4","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1093\/nar\/gkx1239","article-title":"Chemistry, mechanism and clinical status of antisense oligonucleotides and duplex RNAs","volume":"46","author":"Shen","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"2021120508571793000_B5","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1089\/nat.2014.0506","article-title":"Phosphorothioates, essential components of therapeutic oligonucleotides","volume":"24","author":"Eckstein","year":"2014","journal-title":"Nucleic Acid Ther."},{"key":"2021120508571793000_B6","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1021\/acs.accounts.8b00650","article-title":"Re-engineering RNA molecules into Therapeutic Agents","volume":"52","author":"Egli","year":"2019","journal-title":"Acc. Chem. Res."},{"key":"2021120508571793000_B7","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1016\/j.chembiol.2012.07.011","article-title":"Designing chemically modified oligonucleotides for targeted gene silencing","volume":"19","author":"Deleavey","year":"2012","journal-title":"Chem. Biol."},{"key":"2021120508571793000_B8","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1056\/NEJMp1614154","article-title":"Oligonucleotide therapeutics\u2014a new class of cholesterol-lowering drugs","volume":"376","author":"Khvorova","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"2021120508571793000_B9","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1056\/NEJMoa1615758","article-title":"Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol","volume":"376","author":"Ray","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"2021120508571793000_B10","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1056\/NEJMoa1609243","article-title":"Highly durable RNAi therapeutic inhibitor of PCSK9","volume":"376","author":"Fitzgerald","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"2021120508571793000_B11","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/nature03121","article-title":"Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs","volume":"432","author":"Soutschek","year":"2004","journal-title":"Nature"},{"key":"2021120508571793000_B12","doi-asserted-by":"crossref","first-page":"3579","DOI":"10.1093\/nar\/gky145","article-title":"Cellular uptake mediated by epidermal growth factor receptor facilitates the intracellular activity of phosphorothioate-modified antisense oligonucleotides","volume":"46","author":"Wang","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"2021120508571793000_B13","doi-asserted-by":"crossref","first-page":"663","DOI":"10.2174\/1389450115666140321100304","article-title":"Phosphorothioate oligonucleotides: effectiveness and toxicity","volume":"15","author":"Iannitti","year":"2014","journal-title":"Curr. Drug Targets"},{"key":"2021120508571793000_B14","doi-asserted-by":"crossref","first-page":"14754","DOI":"10.1021\/jacs.0c04928","article-title":"The interaction of phosphorothioate-containing RNA targeted drugs with proteins is a critical determinant of the therapeutic effect of these agents","volume":"142","author":"Crooke","year":"2020","journal-title":"J. Am. Chem. Soc."},{"key":"2021120508571793000_B15","doi-asserted-by":"crossref","first-page":"2204","DOI":"10.1093\/nar\/gky060","article-title":"Acute hepatotoxicity of 2\u2032 fluoro-modified 5-10-5 gapmer phosphorothioate oligonucleotides in mice correlates with intracellular protein binding and the loss of DBHS proteins","volume":"46","author":"Shen","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"2021120508571793000_B16","author":"Clercq","year":"1988"},{"key":"2021120508571793000_B17","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1021\/cr60307a003","article-title":"Phosphonates as analogues of natural phosphates","volume":"77","author":"Engel","year":"1977","journal-title":"Chem. Rev."},{"key":"2021120508571793000_B18","doi-asserted-by":"crossref","first-page":"2328","DOI":"10.1021\/jm701260b","article-title":"Prodrugs of phosphates and phosphonates","volume":"51","author":"Hecker","year":"2008","journal-title":"J. Med. Chem."},{"key":"2021120508571793000_B19","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1111\/j.1574-6968.2000.tb09099.x","article-title":"Organophosphonate metabolism by a moderately halophilic bacterial isolate","volume":"186","author":"Hayes","year":"2000","journal-title":"FEMS Microbiol. Lett."},{"key":"2021120508571793000_B20","doi-asserted-by":"crossref","first-page":"6239","DOI":"10.1016\/0040-4039(96)01380-9","article-title":"Synthesis and preliminary biochemical studies with 5\u2032-deoxy-5\u2032-methylidyne phosphonate linked thymidine oligonucleotides","volume":"37","author":"Zhao","year":"1996","journal-title":"Tetrahedron Lett."},{"key":"2021120508571793000_B21","doi-asserted-by":"crossref","first-page":"3215","DOI":"10.1016\/S0040-4039(00)00353-1","article-title":"The \u2018Hirao reduction\u2019 revisited: a procedure for the synthesis of terminal vinyl bromides by the reduction of 1,1-dibromoalkenes","volume":"41","author":"Abbas","year":"2000","journal-title":"Tetrahedron Lett"},{"key":"2021120508571793000_B22","doi-asserted-by":"crossref","first-page":"7725","DOI":"10.1021\/bi025755s","article-title":"Vinylphosphonate internucleotide linkages inhibit the ictivity of PcrA DNA helicase","volume":"41","author":"Bertram","year":"2002","journal-title":"Biochemistry"},{"key":"2021120508571793000_B23","doi-asserted-by":"crossref","first-page":"4513","DOI":"10.1016\/S0040-4039(00)00653-5","article-title":"An improved procedure for the synthesis of vinylphosphonate-linked nucleic acid","volume":"41","author":"Abbas","year":"2000","journal-title":"Tetrahedron Lett."},{"key":"2021120508571793000_B24","doi-asserted-by":"crossref","first-page":"3771","DOI":"10.1093\/nar\/gkh709","article-title":"RPA alleviates the inhibitory effect of vinylphosphonate internucleotide linkage on DNA unwinding by BLM and WRN helicases","volume":"32","author":"Garcia","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"2021120508571793000_B25","doi-asserted-by":"crossref","first-page":"3239","DOI":"10.1021\/bi026985+","article-title":"Effect of vinylphosphonate internucleotide linkages on the cleavage specificity of exonuclease III and on the activity of DNA polymerase I","volume":"42","author":"Doddridge","year":"2003","journal-title":"Biochemistry"},{"key":"2021120508571793000_B26","doi-asserted-by":"crossref","first-page":"1857","DOI":"10.1021\/jm00038a015","article-title":"Synthesis, oral bioavailability determination, and in vitro evaluation of prodrugs of the antiviral agent 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA)","volume":"37","author":"Starrett","year":"1994","journal-title":"J. Med. Chem."},{"key":"2021120508571793000_B27","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/0166-3542(95)00023-F","article-title":"Synthesis, antiviral activity and enzymatic phosphorylation of 9-phosphonopentenyl derivatives of guanine","volume":"27","author":"Nav\u00e9","year":"1995","journal-title":"Antiviral Res."},{"key":"2021120508571793000_B28","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/j.cell.2012.08.014","article-title":"Single-stranded siRNAs Activate RNAi in Animals","volume":"150","author":"Lima","year":"2012","journal-title":"Cell"},{"key":"2021120508571793000_B29","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1021\/cb501028c","article-title":"siRNA conjugates carrying sequentially assembled trivalent N-acetylgalactosamine linked through nucleosides elicit robust gene silencing in vivo in hepatocytes","volume":"10","author":"Matsuda","year":"2015","journal-title":"ACS Chem. Biol."},{"key":"2021120508571793000_B30","doi-asserted-by":"crossref","first-page":"2817","DOI":"10.1016\/j.bmcl.2016.04.063","article-title":"Synergistic effect of phosphorothioate, 5\u2032-vinylphosphonate and GalNAc modifications for enhancing activity of synthetic siRNA","volume":"26","author":"Prakash","year":"2016","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"2021120508571793000_B31","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1002\/cbic.201600130","article-title":"5\u2032-(E)-Vinylphosphonate: a stable phosphate mimic can improve the RNAi activity of siRNA-GalNAc conjugates","volume":"17","author":"Parmar","year":"2016","journal-title":"ChemBioChem"},{"key":"2021120508571793000_B32","doi-asserted-by":"crossref","first-page":"3528","DOI":"10.1093\/nar\/gkw1171","article-title":"siRNA carrying an (E)-vinylphosphonate moiety at the 5\u2032-end of the guide strand augments gene silencing by enhanced binding to human Argonaute-2","volume":"45","author":"Elkayam","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"2021120508571793000_B33","doi-asserted-by":"crossref","first-page":"2993","DOI":"10.1093\/nar\/gkv162","article-title":"Identification of metabolically stable 5\u2032-phosphate analogs that support single strand siRNA activity","volume":"43","author":"Prakash","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"2021120508571793000_B34","doi-asserted-by":"crossref","first-page":"7581","DOI":"10.1093\/nar\/gkx507","article-title":"5\u2032-Vinylphosphonate improves tissue accumulation and efficacy of conjugated siRNAs in vivo","volume":"45","author":"Haraszti","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"2021120508571793000_B35","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1021\/acs.jmedchem.7b01147","article-title":"Facile synthesis, geometry, and 2\u2032-substituent-dependent in vivo activity of 5\u2032-(E)- and 5\u2032-(Z)-vinylphosphonate-modified siRNA conjugates","volume":"61","author":"Parmar","year":"2018","journal-title":"J. Med. Chem."},{"key":"2021120508571793000_B36","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1016\/0896-6273(95)90346-1","article-title":"Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons","volume":"14","author":"DiFiglia","year":"1995","journal-title":"Neuron"},{"key":"2021120508571793000_B37","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1093\/nar\/gky1239","article-title":"Diverse lipid conjugates for functional extra-hepatic siRNA delivery in vivo","volume":"47","author":"Biscans","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"2021120508571793000_B38","doi-asserted-by":"crossref","first-page":"3365","DOI":"10.1021\/ol0166045","article-title":"Commercially available 5\u2032-DMT phosphoramidites as reagents for the synthesis of vinylphosphonate-linked oligonucleic acids","volume":"3","author":"Abbas","year":"2001","journal-title":"Org. Lett."},{"key":"2021120508571793000_B39","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1021\/jm049167j","article-title":"Fully 2\u2032-modified oligonucleotide duplexes with improved in vitro potency and stability compared to unmodified small interfering RNA","volume":"48","author":"Allerson","year":"2005","journal-title":"J. Med. Chem."},{"key":"2021120508571793000_B40","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1016\/j.ymthe.2017.12.021","article-title":"Advanced siRNA designs further improve in vivo performance of GalNAc-siRNA conjugates","volume":"26","author":"Foster","year":"2018","journal-title":"Mol. Ther."},{"key":"2021120508571793000_B41","doi-asserted-by":"crossref","first-page":"3745","DOI":"10.1021\/jo00331a039","article-title":"Reduction of gem-dibromides with diethyl phosphite","volume":"46","author":"Hirao","year":"1981","journal-title":"J. Org. Chem."},{"key":"2021120508571793000_B42","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.1093\/nar\/gky037","article-title":"Comparison of partially and fully chemically-modified siRNA in conjugate-mediated delivery in vivo","volume":"46","author":"Hassler","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"2021120508571793000_B43","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/nar\/gkw1005","article-title":"Visualization of self-delivering hydrophobically modified siRNA cellular internalization","volume":"45","author":"Ly","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"2021120508571793000_B44","doi-asserted-by":"crossref","first-page":"16958","DOI":"10.1021\/ja505986a","article-title":"Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing","volume":"136","author":"Nair","year":"2014","journal-title":"J. Am. Chem. Soc."},{"key":"2021120508571793000_B45","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1021\/acs.bioconjchem.5b00265","article-title":"Effcient synthesis and biological evaluation of 5\u2032-GalNAc conjugated antisense oligonucleotides","volume":"26","author":"\u00d8stergaard","year":"2015","journal-title":"Bioconjug. Chem."},{"key":"2021120508571793000_B46","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1002\/cbic.201500023","article-title":"Hepatocyte-specific delivery of siRNAs conjugated to novel non-nucleosidic trivalent N-acetylgalactosamine elicits robust gene silencing in vivo","volume":"16","author":"Rajeev","year":"2015","journal-title":"Chembiochem."},{"key":"2021120508571793000_B47","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1038\/s41587-019-0205-0","article-title":"A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system","volume":"37","author":"Alterman","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"2021120508571793000_B48","doi-asserted-by":"crossref","first-page":"e266","DOI":"10.1038\/mtna.2015.38","article-title":"Hydrophobically modified siRNAs silence Hutingtin mRNA in primary neurons and mouse brain","volume":"4","author":"Alterman","year":"2015","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"2021120508571793000_B49","doi-asserted-by":"crossref","first-page":"4247","DOI":"10.1021\/jm050044o","article-title":"Positional effect of chemical modifications on short interference RNA activity in mammalian cells","volume":"48","author":"Prakash","year":"2005","journal-title":"J. Med. Chem."},{"key":"2021120508571793000_B50","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1016\/j.molcel.2011.02.004","article-title":"Coupled 5\u2032 nucleotide recognition and processivity in Xrn1-mediated mRNA decay","volume":"41","author":"Jinek","year":"2011","journal-title":"Mol. Cell"},{"key":"2021120508571793000_B51","doi-asserted-by":"crossref","first-page":"9.6.1","DOI":"10.1002\/0471142700.nc0906s56","article-title":"In vitro selection using modified or unnatural nucleotides","volume":"56","author":"Stovall","year":"2014","journal-title":"Curr. Protoc. Nucleic Acid Chem."},{"key":"2021120508571793000_B52","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/nrneurol.2014.24","article-title":"Huntington disease: natural history, biomarkers and prospects for therapeutics","volume":"10","author":"Ross","year":"2014","journal-title":"Nat. Rev. Neurol."},{"key":"2021120508571793000_B53","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.expneurol.2009.09.017","article-title":"Huntington's disease: silencing a brutal killer","volume":"220","author":"Pfister","year":"2009","journal-title":"Exp. Neurol."},{"key":"2021120508571793000_B54","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1016\/j.cub.2009.03.030","article-title":"Five siRNAs targeting three SNPs in Huntingin may provide therapy for three-quarters of Huntington's disease patients","volume":"19","author":"Pfister","year":"2009","journal-title":"Curr. Biol."},{"key":"2021120508571793000_B55","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1146\/annurev.biophys.34.040204.144521","article-title":"From \u201cSimple\u201d DNA-protein interactions to the macromolecular machines of gene expression","volume":"36","author":"von\u00a0Hippel","year":"2007","journal-title":"Annu. Rev. Biophys. Biomol. Struct."},{"key":"2021120508571793000_B56","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1056\/NEJMoa1900907","article-title":"Phase 1\u20132a IONIS-HTTRx study site teams, targeting Huntingtin expression in patients with Huntington's disease","volume":"380","author":"Tabrizi","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"2021120508571793000_B57","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1261\/rna.5103703","article-title":"siRNA function in RNAi: a chemical modification analysis","volume":"9","author":"Chiu","year":"2003","journal-title":"RNA"},{"key":"2021120508571793000_B58","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1126\/science.1258040","article-title":"Structural basis for MicroRNA targeting","volume":"346","author":"Schirle","year":"2014","journal-title":"Science"},{"key":"2021120508571793000_B59","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/j.cell.2005.11.006","article-title":"RNAi: RISC gets loaded","volume":"123","author":"Preall","year":"2005","journal-title":"Cell"},{"key":"2021120508571793000_B60","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1016\/j.tibs.2010.03.009","volume":"35","author":"Kawamata","year":"2010","journal-title":"Trends Biochem. Sci."},{"key":"2021120508571793000_B61","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.cell.2015.06.029","article-title":"Single-molecule imaging reveals that Argonaute reshapes the binding properties of its nucleic acid guides","volume":"162","author":"Salomon","year":"2015","journal-title":"Cell"},{"key":"2021120508571793000_B62","doi-asserted-by":"crossref","first-page":"8694","DOI":"10.1021\/jacs.6b04454","article-title":"Structural analysis of human Argonaute-2 bound to a modified siRNA guide","volume":"138","author":"Schirle","year":"2016","journal-title":"J. Am. Chem. Soc."},{"key":"2021120508571793000_B63","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1038\/nature07315","article-title":"Structure of the guide-strand-containing argonaute silencing complex","volume":"456","author":"Wang","year":"2008","journal-title":"Nature"},{"key":"2021120508571793000_B64","doi-asserted-by":"crossref","first-page":"8537","DOI":"10.1021\/jacs.7b02694","article-title":"Chirality dependent potency enhancement and structural impact of glycol nucleic acid modification on siRNA","volume":"139","author":"Schlegel","year":"2017","journal-title":"J. Am. Chem. Soc."},{"key":"2021120508571793000_B65","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1093\/nar\/gkp913","article-title":"Analysis of acyclic nucleoside modifications in siRNAs finds sensitivity at position 1 that is restored by 5\u2032-terminal phosphorylation both in vitro and in vivo","volume":"38","author":"Kenski","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"2021120508571793000_B66","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1038\/nature02519","article-title":"Structural basis for overhang- specific small interfering RNA recognition by the PAZ domain","volume":"429","author":"Ma","year":"2004","journal-title":"Nature"},{"key":"2021120508571793000_B67","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1089\/nat.2015.0547","article-title":"Allele-selective inhibition of mutant Huntingtin with 2-thio- and C5- triazolylphenyl-deoxythymidine-modified antisense oligonucleotides","volume":"25","author":"\u00d8stergaard","year":"2015","journal-title":"Nucleic Acid Ther."},{"key":"2021120508571793000_B68","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.omtn.2017.02.001","article-title":"Fluorinated nucleotide modifications modulate allele selectivity of SNP-targeting antisense oligonucleotides","volume":"7","author":"\u00d8stergaard","year":"2017","journal-title":"Mol. Ther. Nucleic Acids."},{"key":"2021120508571793000_B69","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1038\/s41467-018-02989-4","article-title":"Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity","volume":"9","author":"Janas","year":"2018","journal-title":"Nat. Commun."}],"container-title":["Nucleic Acids Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/nar\/article-pdf\/49\/21\/12069\/41503869\/gkab1126.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/nar\/article-pdf\/49\/21\/12069\/41503869\/gkab1126.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,5]],"date-time":"2021-12-05T08:59:32Z","timestamp":1638694772000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/nar\/article\/49\/21\/12069\/6439666"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,25]]},"references-count":69,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2021,11,25]]},"published-print":{"date-parts":[[2021,12,2]]}},"URL":"https:\/\/doi.org\/10.1093\/nar\/gkab1126","relation":{},"ISSN":["0305-1048","1362-4962"],"issn-type":[{"value":"0305-1048","type":"print"},{"value":"1362-4962","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,12,2]]},"published":{"date-parts":[[2021,11,25]]}}}