{"doi":"10.1101/2021.12.24.474126","title":"Strain dependent structural effects and <i>in vivo</i> efficacy of enterovirus-D68 inhibitors","abstract":"Abstract Acute flaccid myelitis (AFM) leads to loss of limb control in young children and is likely due to Enterovirus-D68 (EV-D68), for which there is no current treatment. We have developed a lead isoxazole-3-carboxamide analog of pleconaril (11526092) which displayed potent inhibition of the pleconaril-resistant CVB3-Woodruff (IC 50 6-20 nM), EV-D68 (IC 50 58 nM), and other enteroviruses. A mouse respiratory model of EV-D68 infection, in which pleconaril is inactive, showed decreased viremia of 3 log units as well as statistically significant 1 log reduction in lung titer reduction at day 5 after treatment with 11526092. A cryo-electron microscopy (cryo-EM) structure of EV-D68 in complex with 11526092 suggests that the increased potency may be due to additional hydrophobic interactions. Cryo-EM structures of 11526092 and pleconaril demonstrate destabilization of EV-D68 (MO strain) compared to the previously described stabilization of EV-D68 (Fermon strain) with pleconaril, illustrating clear strain dependent mechanisms of this molecule. 11526092 represents a more potent inhibitor in vitro with in vivo efficacy providing a potential future treatment for EV-D68 and AFM, suggesting an improvement over pleconaril for further optimization. One-Sentence Summary 11526092 demonstrates protein destabilization, improved in vitro potency and in vivo efficacy when compared with pleconaril against EV-D68.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":228266,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9632,"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":327014,"name":"Jianing Fu","orcid":"0000-0002-9348-2373","position":1,"is_corresponding":false},{"id":833098,"name":"Barbara Sherry","orcid":"0000-0001-9858-6094","position":2,"is_corresponding":false},{"id":107693,"name":"E. Bart Tarbet","orcid":"0000-0002-4255-9094","position":3,"is_corresponding":false},{"id":107688,"name":"Brett L. Hurst","orcid":"0000-0003-1025-5878","position":4,"is_corresponding":false},{"id":430115,"name":"Olga Riabova","orcid":"0000-0002-3794-6495","position":5,"is_corresponding":false},{"id":833099,"name":"Elena Kazakova","orcid":"0000-0002-8546-7333","position":6,"is_corresponding":false},{"id":833100,"name":"Anna Egorova","orcid":"0000-0002-6345-7812","position":7,"is_corresponding":false},{"id":476727,"name":"Penny Clarke","orcid":"0000-0001-5540-2910","position":8,"is_corresponding":false},{"id":833455,"name":"J. Smith Leser","orcid":null,"position":9,"is_corresponding":false},{"id":833101,"name":"Joshua Frost","orcid":"0000-0001-6517-4966","position":10,"is_corresponding":false},{"id":833102,"name":"Michael J. Rudy","orcid":"0000-0002-3936-6849","position":11,"is_corresponding":false},{"id":369318,"name":"Kenneth L. Tyler","orcid":"0000-0003-3294-5888","position":12,"is_corresponding":false},{"id":327015,"name":"Thomas Klose","orcid":"0000-0002-2150-9792","position":13,"is_corresponding":false},{"id":314297,"name":"Richard Kühn","orcid":"0000-0003-4148-1026","position":14,"is_corresponding":false},{"id":321356,"name":"Vadim Makarov","orcid":"0000-0001-8746-2694","position":15,"is_corresponding":false},{"id":272341,"name":"Sean Ekins","orcid":"0000-0002-5691-5790","position":16,"is_corresponding":false},{"id":323047,"name":"Thomas R. Lane","orcid":"0000-0001-9240-4763","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-18T23:54:50.414605Z","pmid":null,"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":[]}