{"doi":"10.1093/nar/gkab1126","title":"Structurally constrained phosphonate internucleotide linkage impacts oligonucleotide-enzyme interaction, and modulates siRNA activity and allele specificity","abstract":"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 and (iii) a new strategy for highly selective SNP-discriminating siRNAs.","journal":"Nucleic Acids Research","year":2021,"id":177956,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":20,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9516,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":667631,"name":"Samuel Hildebrand","orcid":"0000-0002-6633-3495","position":1,"is_corresponding":false},{"id":302203,"name":"Sarah M. Davis","orcid":"0000-0001-5758-1924","position":2,"is_corresponding":false},{"id":722997,"name":"Rachael Miller","orcid":"0000-0002-4594-0640","position":3,"is_corresponding":false},{"id":722998,"name":"Faith Conroy","orcid":"0000-0002-9934-7308","position":4,"is_corresponding":false},{"id":662289,"name":"Ellen Sapp","orcid":"0000-0002-0905-4940","position":5,"is_corresponding":false},{"id":302202,"name":"Jillian Caiazzi","orcid":"0000-0002-7077-2116","position":6,"is_corresponding":false},{"id":398076,"name":"Julia F. Alterman","orcid":"0000-0002-6195-0857","position":7,"is_corresponding":false},{"id":722999,"name":"Loïc Roux","orcid":"0000-0002-6099-0427","position":8,"is_corresponding":false},{"id":398074,"name":"Dimas Echeverria","orcid":"0000-0002-1040-0855","position":9,"is_corresponding":false},{"id":398073,"name":"Matthew Hassler","orcid":"0000-0001-7897-6503","position":10,"is_corresponding":false},{"id":542519,"name":"Edith L. Pfister","orcid":"0000-0002-0345-7773","position":11,"is_corresponding":false},{"id":662295,"name":"Marian DiFiglia","orcid":"0000-0003-4155-8177","position":12,"is_corresponding":false},{"id":474623,"name":"Neil Aronin","orcid":"0000-0003-1209-8925","position":13,"is_corresponding":false},{"id":302206,"name":"Anastasia Khvorova","orcid":"0000-0001-6928-8071","position":14,"is_corresponding":false},{"id":722996,"name":"Ken Yamada","orcid":"0000-0002-5714-8298","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":null,"created_at":"2026-07-18T23:47:36.112170Z","pmid":"34850120","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}