{"doi":"10.1128/jvi.02116-10","title":"Antiviral Stilbene 1,2-Diamines Prevent Initiation of Hepatitis C Virus RNA Replication at the Outset of Infection","abstract":"<jats:title>ABSTRACT</jats:title><jats:p>The recent development of a cell culture model of hepatitis C virus (HCV) infection based on the JFH-1 molecular clone has enabled discovery of new antiviral agents. Using a cell-based colorimetric screening assay to interrogate a 1,200-compound chemical library for anti-HCV activity, we identified a family of 1,2-diamines derived from<jats:italic>trans</jats:italic>-stilbene oxide that prevent HCV infection at nontoxic, low micromolar concentrations in cell culture. Structure-activity relationship analysis of ∼300 derivatives synthesized using click chemistry yielded compounds with greatly enhanced low nanomolar potency and a &gt;1,000:1 therapeutic ratio. Using surrogate models of HCV infection, we showed that the compounds selectively block the initiation of replication of incoming HCV RNA but have no impact on viral entry, primary translation, or ongoing HCV RNA replication, nor do they suppress persistent HCV infection. Selection of an escape variant revealed that NS5A is directly or indirectly targeted by this compound. In summary, we have identified a family of HCV inhibitors that target a critical step in the establishment of HCV infection in which NS5A translated<jats:named-content content-type=\"genus-species\">de novo</jats:named-content>from an incoming genomic HCV RNA template is required to initiate the replication of this important human pathogen.</jats:p>","journal":"Journal of Virology","year":2011,"id":629813,"datarank":0.44166584687496613,"base_score":2.9444389791664403,"endowment":2.9444389791664403,"self_citation_contribution":0.44166584687496613,"citation_network_contribution":0.0,"self_endowment_contribution":0.44166584687496613,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1631256,"name":"Suresh M. Pitram","orcid":null,"position":1,"is_corresponding":false},{"id":1631257,"name":"Marlene Dreux","orcid":null,"position":2,"is_corresponding":false},{"id":1374313,"name":"Larissa B. Krasnova","orcid":"0000-0002-1657-4311","position":3,"is_corresponding":false},{"id":575243,"name":"Christina Whitten-Bauer","orcid":null,"position":4,"is_corresponding":false},{"id":1023915,"name":"Jiajia Dong","orcid":"0000-0001-9908-2699","position":5,"is_corresponding":false},{"id":1631258,"name":"Josan Chung","orcid":null,"position":6,"is_corresponding":false},{"id":76012,"name":"Valery V. Fokin","orcid":"0000-0001-7323-2177","position":7,"is_corresponding":false},{"id":74387,"name":"K. Barry Sharpless","orcid":"0000-0001-6051-1599","position":8,"is_corresponding":false},{"id":1259309,"name":"Francis V. Chisari","orcid":"0000-0002-4832-1044","position":9,"is_corresponding":false},{"id":1631255,"name":"Pablo Gastaminza","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Antiviral Stilbene 1,2-Diamines Prevent Initiation of Hepatitis C Virus RNA Replication at the Outset of Infection","abstract":"<jats:title>ABSTRACT</jats:title><jats:p>The recent development of a cell culture model of hepatitis C virus (HCV) infection based on the JFH-1 molecular clone has enabled discovery of new antiviral agents. Using a cell-based colorimetric screening assay to interrogate a 1,200-compound chemical library for anti-HCV activity, we identified a family of 1,2-diamines derived from<jats:italic>trans</jats:italic>-stilbene oxide that prevent HCV infection at nontoxic, low micromolar concentrations in cell culture. Structure-activity relationship analysis of ∼300 derivatives synthesized using click chemistry yielded compounds with greatly enhanced low nanomolar potency and a &gt;1,000:1 therapeutic ratio. Using surrogate models of HCV infection, we showed that the compounds selectively block the initiation of replication of incoming HCV RNA but have no impact on viral entry, primary translation, or ongoing HCV RNA replication, nor do they suppress persistent HCV infection. Selection of an escape variant revealed that NS5A is directly or indirectly targeted by this compound. In summary, we have identified a family of HCV inhibitors that target a critical step in the establishment of HCV infection in which NS5A translated<jats:named-content content-type=\"genus-species\">de novo</jats:named-content>from an incoming genomic HCV RNA template is required to initiate the replication of this important human pathogen.</jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"21430055","pmcid":"PMC3094966","openalex_id":null,"authors":[],"funders":[{"funder_name":"NIAID NIH HHS","grant_id":"R01 AI079043","title":null},{"funder_name":"NCI NIH HHS","grant_id":"R01 CA108304","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"R01 GM087620","title":null},{"funder_name":"NIAID NIH HHS","grant_id":"R01-AI079043","title":null},{"funder_name":"NCI NIH HHS","grant_id":"R01-CA108304","title":null}],"total_grants":5,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"green","license":"https://journals.asm.org/non-commercial-tdm-license","oa_locations":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/3094966","host_type":"repository"},{"url":"https://journals.asm.org/doi/pdf/10.1128/JVI.02116-10","host_type":"publisher"}],"fields_of_study":[],"mesh_terms":["Cell Line","Hepatocytes","Humans","Hepacivirus","Diamines","Stilbenes","Viral Nonstructural Proteins","RNA, Viral","Antiviral Agents","Microbial Sensitivity Tests","Drug Evaluation, Preclinical","Drug Resistance, Viral","Virus Replication","Cell Survival","Structure-Activity Relationship","RNA-Dependent RNA Polymerase"],"keywords":[],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-05T19:45:15.467879Z","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":[]}