{"doi":"10.1073/pnas.2426922122","title":"Mechanistic insights into dengue virus inhibition by a clinical trial compound NITD-688","abstract":"Dengue, caused by the dengue virus (DENV), presents a significant public health challenge with limited effective treatments. NITD-688 is a potent panserotype DENV inhibitor currently in Phase II clinical trials. However, its mechanism of action is not fully understood. Here, we present the molecular details of how NITD-688 inhibits DENV. NITD-688 binds directly to the nonstructural protein 4B (NS4B) with nanomolar affinities across all four DENV serotypes and specifically disrupts the interaction between NS4B and nonstructural protein 3 (NS3) without significantly changing the interactions between NS4B and other viral or host proteins. NS4B mutations that confer resistance to NITD-688 reduce both NITD-688 binding to NS4B and disruption of the NS4B/NS3 interaction. Specifically, NITD-688 blocks the interaction of NS3 with a cytosolic loop within NS4B. This inhibits the formation of new NS4B/NS3 complexes and disrupts preexisting complexes in vitro and DENV-infected cells, ultimately inhibiting viral replication. Consistent with this mechanism, NITD-688 retains greater potency in cellular assays with delayed treatment compared to JNJ-1802, another NS4B inhibitor that has been studied in Phase II clinical trials. Together, these findings provide critical insights into the mechanism of action of NITD-688, facilitating the development of novel flavivirus NS4B inhibitors and informing future clinical interventions against DENV.","journal":"Proceedings of the National Academy of Sciences","year":2025,"id":515611,"datarank":0.3958585994422889,"base_score":2.639057329615259,"endowment":2.639057329615259,"self_citation_contribution":0.3958585994422889,"citation_network_contribution":0.0,"self_endowment_contribution":0.3958585994422889,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.959,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1202782,"name":"Long Sun","orcid":"0000-0003-4889-4624","position":2,"is_corresponding":false},{"id":1379947,"name":"Luciana de Souza Fernandes","orcid":"0000-0003-4327-9454","position":3,"is_corresponding":false},{"id":656792,"name":"YH Wang","orcid":"0000-0001-9753-5535","position":4,"is_corresponding":false},{"id":105308,"name":"Jing Zou","orcid":"0000-0002-8098-7284","position":6,"is_corresponding":false},{"id":879392,"name":"Samuel J. Franklin","orcid":"0000-0002-6965-1157","position":7,"is_corresponding":false},{"id":1030556,"name":"Yanping Hu","orcid":"0009-0006-8820-7437","position":8,"is_corresponding":false},{"id":1233266,"name":"Lee K. Palmer","orcid":"0000-0002-7532-2341","position":9,"is_corresponding":false},{"id":59676,"name":"Jason Yeung","orcid":"0000-0002-4202-9771","position":10,"is_corresponding":false},{"id":1380537,"name":"Daniela Barriga","orcid":null,"position":11,"is_corresponding":false},{"id":250363,"name":"William K. Russell","orcid":"0000-0003-1931-4555","position":12,"is_corresponding":false},{"id":526907,"name":"Stephanie Moquin","orcid":"0000-0002-8696-4315","position":13,"is_corresponding":false},{"id":38215,"name":"Pei‐Yong Shi","orcid":"0000-0001-5553-1616","position":14,"is_corresponding":false},{"id":545626,"name":"Colin K. Skepper","orcid":"0000-0002-6771-2024","position":15,"is_corresponding":false},{"id":105317,"name":"Xuping Xie","orcid":"0000-0003-0918-016X","position":16,"is_corresponding":false},{"id":864882,"name":"Yan Wang","orcid":"0000-0002-0452-6750","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:48:39.436300Z","pmid":"40153462","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":[]}