{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T02:28:29Z","timestamp":1793413709900,"version":"4.5.0"},"reference-count":65,"publisher":"National Academy of Sciences","issue":"13","license":[{"start":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T00:00:00Z","timestamp":1743120000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["U19AI171413"],"award-info":[{"award-number":["U19AI171413"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004917","name":"Cancer Prevention Research Institute of Texas","doi-asserted-by":"crossref","award":["RP190682"],"award-info":[{"award-number":["RP190682"]}],"id":[{"id":"10.13039\/100004917","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,4,1]]},"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.1073\/pnas.2426922122","type":"journal-article","created":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T13:37:45Z","timestamp":1743169065000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":22,"title":["Mechanistic insights into dengue virus inhibition by a clinical trial compound NITD-688"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0452-6750","authenticated-orcid":false,"given":"Yan","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch","place":["Galveston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4889-4624","authenticated-orcid":false,"given":"Long","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch","place":["Galveston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4327-9454","authenticated-orcid":false,"given":"Luciana","family":"Fernandes","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch","place":["Galveston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9753-5535","authenticated-orcid":false,"given":"Yu-Hsiu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Texas Medical Branch","place":["Galveston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8098-7284","authenticated-orcid":false,"given":"Jing","family":"Zou","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch","place":["Galveston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6965-1157","authenticated-orcid":false,"given":"Samuel J.","family":"Franklin","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch","place":["Galveston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8820-7437","authenticated-orcid":false,"given":"Yanping","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch","place":["Galveston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee K.","family":"Palmer","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Texas Medical Branch","place":["Galveston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Yeung","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Texas Medical Branch","place":["Galveston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Barriga","sequence":"additional","affiliation":[{"name":"Global Health, Biomedical Research, Novartis","place":["Emeryville"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1931-4555","authenticated-orcid":false,"given":"William K.","family":"Russell","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Texas Medical Branch","place":["Galveston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie A.","family":"Moquin","sequence":"additional","affiliation":[{"name":"Global Health, Biomedical Research, Novartis","place":["Emeryville"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-Yong","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Texas Medical Branch","place":["Galveston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin","family":"Skepper","sequence":"additional","affiliation":[{"name":"Global Health, Biomedical Research, Novartis","place":["Emeryville"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0918-016X","authenticated-orcid":false,"given":"Xuping","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch","place":["Galveston"]},{"name":"Sealy Institute for Drug Discovery, University of Texas Medical Branch","place":["Galveston"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,3,28]]},"reference":[{"key":"e_1_3_5_1_2","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/S0140-6736(24)01542-3","article-title":"Dengue: The threat to health now and in the future","volume":"404","author":"The L.","year":"2024","unstructured":"L. The, Dengue: The threat to health now and in the future. Lancet 404, 311 (2024).","journal-title":"Lancet"},{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature12060"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)32560-1"},{"key":"e_1_3_5_4_2","first-page":"299","article-title":"Epidemiology of dengue: Past, present and future prospects","volume":"5","author":"Murray N. E. A.","year":"2013","unstructured":"N. E. A. Murray, M. B. Quam, A. Wilder-Smith, Epidemiology of dengue: Past, present and future prospects. Clin. Epidemiol. 5, 299\u2013309 (2013).","journal-title":"Clin. Epidemiol."},{"key":"e_1_3_5_5_2","volume-title":"Global Strategy for Dengue Prevention and Control 2012\u20132020","author":"World Health Organization","year":"2012","unstructured":"World Health Organization, Global Strategy for Dengue Prevention and Control 2012\u20132020 (World Health Organization, 2012)."},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(16)00026-8"},{"key":"e_1_3_5_7_2","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1016\/S1473-3099(20)30601-0","article-title":"Risk predictors of progression to severe disease during the febrile phase of dengue: A systematic review and meta-analysis","volume":"21","author":"Sangkaew S.","year":"2021","unstructured":"S. Sangkaew , Risk predictors of progression to severe disease during the febrile phase of dengue: A systematic review and meta-analysis. Lancet Infect. Dis. 21, 1014\u20131026 (2021).","journal-title":"Lancet Infect. Dis."},{"key":"e_1_3_5_8_2","volume-title":"Disease Outbreak News; Dengue\u2013Global Situation","author":"World Health Organization","year":"2023","unstructured":"World Health Organization, Disease Outbreak News; Dengue\u2013Global Situation (World Health Organization, 2023)."},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.1983.32.154"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1080\/21645515.2019.1658503"},{"key":"e_1_3_5_11_2","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1093\/cid\/ciab864","article-title":"Three-year efficacy and safety of takeda\u2019s dengue vaccine candidate (TAK-003)","volume":"75","author":"Rivera L.","year":"2022","unstructured":"L. Rivera , Three-year efficacy and safety of takeda\u2019s dengue vaccine candidate (TAK-003). Clin. Infect. Dis. 75, 107\u2013117 (2022).","journal-title":"Clin. Infect. Dis."},{"key":"e_1_3_5_12_2","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1126\/scitranslmed.aaf1517","article-title":"The live attenuated dengue vaccine TV003 elicits complete protection against dengue in a human challenge model","volume":"8","author":"Kirkpatrick B. D.","year":"2016","unstructured":"B. D. Kirkpatrick , The live attenuated dengue vaccine TV003 elicits complete protection against dengue in a human challenge model. Sci. Transl. Med. 8, 330\u2013336 (2016).","journal-title":"Sci. Transl. Med."},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(20)30023-2"},{"key":"e_1_3_5_14_2","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/S1473-3099(23)00520-0","article-title":"Safety and durable immunogenicity of the TV005 tetravalent dengue vaccine, across serotypes and age groups, in dengue-endemic Bangladesh: A randomised, controlled trial","volume":"24","author":"Walsh M. R.","year":"2024","unstructured":"M. R. Walsh , Safety and durable immunogenicity of the TV005 tetravalent dengue vaccine, across serotypes and age groups, in dengue-endemic Bangladesh: A randomised, controlled trial. Lancet Infect. Dis. 24, 150\u2013160 (2024).","journal-title":"Lancet Infect. Dis."},{"key":"e_1_3_5_15_2","doi-asserted-by":"crossref","DOI":"10.1016\/S2542-5196(19)30057-9","article-title":"Evaluation of intensified dengue control measures with interrupted time series analysis in the panadura medical officer of health division in sri lanka: A case study and cost-effectiveness analysis","volume":"3","author":"Liyanage P.","year":"2019","unstructured":"P. Liyanage , Evaluation of intensified dengue control measures with interrupted time series analysis in the panadura medical officer of health division in sri lanka: A case study and cost-effectiveness analysis. Lancet Planet Health 3, e211\u2013e218 (2019).","journal-title":"Lancet Planet Health"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid2410.180069"},{"key":"e_1_3_5_17_2","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/S1473-3099(24)00030-6","article-title":"An observer-blind, randomised, placebo-controlled, phase 1, single ascending dose study of dengue monoclonal antibody in healthy adults in Australia","volume":"24","author":"Gunale B.","year":"2024","unstructured":"B. Gunale , An observer-blind, randomised, placebo-controlled, phase 1, single ascending dose study of dengue monoclonal antibody in healthy adults in Australia. Lancet Infect. Dis. 24, 639\u2013649 (2024), 10.1016\/S1473-3099(24)00030-6.","journal-title":"Lancet Infect. Dis."},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2013.09.013"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abb2181"},{"key":"e_1_3_5_20_2","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1038\/s41586-023-05790-6","article-title":"Blocking NS3\u2013NS4B interaction inhibits dengue virus in non-human primates","volume":"615","author":"Goethals O.","year":"2023","unstructured":"O. Goethals , Blocking NS3\u2013NS4B interaction inhibits dengue virus in non-human primates. Nature 615, 678\u2013686 (2023).","journal-title":"Nature"},{"key":"e_1_3_5_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03990-6"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-023-00914-1"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-022-00608-8"},{"key":"e_1_3_5_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2018.12.016"},{"key":"e_1_3_5_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.73.6.4611-4621.1999"},{"key":"e_1_3_5_26_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M512697200"},{"key":"e_1_3_5_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2023.06.023"},{"key":"e_1_3_5_28_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00206-16"},{"key":"e_1_3_5_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2019.09.015"},{"key":"e_1_3_5_30_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.79.13.8004-8013.2005"},{"key":"e_1_3_5_31_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02188-08"},{"key":"e_1_3_5_32_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.65.5.2467-2475.1991"},{"key":"e_1_3_5_33_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.73.4.3108-3116.1999"},{"key":"e_1_3_5_34_2","doi-asserted-by":"publisher","DOI":"10.1261\/rna.1609709"},{"key":"e_1_3_5_35_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00814-06"},{"key":"e_1_3_5_36_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M104248200"},{"key":"e_1_3_5_37_2","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1128\/JVI.06225-11","article-title":"Ligand-bound structures of the dengue virus protease reveal the active conformation","volume":"86","author":"Noble C. G.","year":"2012","unstructured":"C. G. Noble, C. C. Seh, A. T. Chao, P. Y. Shi, Ligand-bound structures of the dengue virus protease reveal the active conformation. J. Virol. 86, 438\u2013446 (2012).","journal-title":"J. Virol."},{"key":"e_1_3_5_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2015.04.010"},{"key":"e_1_3_5_39_2","doi-asserted-by":"crossref","DOI":"10.1128\/AAC.00988-21","article-title":"Evaluation of AT-752, a double prodrug of a guanosine nucleotide analog with in vitro and in vivo activity against dengue and other flaviviruses","volume":"65","author":"Good S. S.","year":"2021","unstructured":"S. S. Good , Evaluation of AT-752, a double prodrug of a guanosine nucleotide analog with in vitro and in vivo activity against dengue and other flaviviruses. Antimicrob. Agents chemother. 65, e0098821 (2021).","journal-title":"Antimicrob. Agents chemother."},{"key":"e_1_3_5_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2022.08.005"},{"key":"e_1_3_5_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2022.105423"},{"key":"e_1_3_5_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.101597"},{"key":"e_1_3_5_43_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00157-12"},{"key":"e_1_3_5_44_2","doi-asserted-by":"crossref","first-page":"3471","DOI":"10.1128\/JVI.03454-14","article-title":"Mapping the Interactions between the NS4B and NS3 proteins of dengue virus","volume":"89","author":"Zou J.","year":"2015","unstructured":"J. Zou , Mapping the Interactions between the NS4B and NS3 proteins of dengue virus. J. Virol. 89, 3471\u20133483 (2015).","journal-title":"J. Virol."},{"key":"e_1_3_5_45_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.03453-14"},{"key":"e_1_3_5_46_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.05468-11"},{"key":"e_1_3_5_47_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00855-15"},{"key":"e_1_3_5_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2013.05.011"},{"key":"e_1_3_5_49_2","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1093\/cid\/ciad284","article-title":"Safety, tolerability, and pharmacokinetics of JNJ-1802, a pan-serotype dengue direct antiviral small molecule, in a phase 1, double-blind, randomized, dose-escalation study in healthy volunteers","volume":"77","author":"Ackaert O.","year":"2023","unstructured":"O. Ackaert , Safety, tolerability, and pharmacokinetics of JNJ-1802, a pan-serotype dengue direct antiviral small molecule, in a phase 1, double-blind, randomized, dose-escalation study in healthy volunteers. Clin. Infect. Dis. 77, 857\u2013865 (2023).","journal-title":"Clin. Infect. Dis."},{"key":"e_1_3_5_50_2","doi-asserted-by":"crossref","first-page":"D678","DOI":"10.1093\/nar\/gkac1003","article-title":"Introducing the bacterial and viral bioinformatics resource center (BV-BRC): A resource combining PATRIC IRD and ViPR","volume":"51","author":"Olson R. D.","year":"2023","unstructured":"R. D. Olson , Introducing the bacterial and viral bioinformatics resource center (BV-BRC): A resource combining PATRIC IRD and ViPR. Nucleic Acids Res. 51, D678\u2013d689 (2023).","journal-title":"Nucleic Acids Res."},{"key":"e_1_3_5_51_2","unstructured":"H. D. Johnston \u201cThe thermodynamics (log K [Delta]H\u00b0 [Delta]S\u00b0 [Delta]Cp\u00b0) of metal ligand interaction in aqueous solution.|nI.|p Design and construction of an isothermal titration calorimeter.|nII.|pThe interaction of cyanide ion with bivalent nickel zinc cadmium and mercury.|nIII.|pThe interaction of glycinate ion with bivalent manganese iron cobalt nickel copper zinc and cadmium\u201d Doctoral dissertation Brigham Young University Provo UT (1968)."},{"key":"e_1_3_5_52_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02782-13"},{"key":"e_1_3_5_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.11.028"},{"key":"e_1_3_5_54_2","doi-asserted-by":"publisher","DOI":"10.2174\/138620709789104915"},{"key":"e_1_3_5_55_2","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.virol.2013.12.025","article-title":"Generation and characterization of mouse monoclonal antibodies against NS4B protein of dengue virus","volume":"450","author":"Xie X.","year":"2014","unstructured":"X. Xie , Generation and characterization of mouse monoclonal antibodies against NS4B protein of dengue virus. Virology 450, 250\u2013257 (2014).","journal-title":"Virology"},{"key":"e_1_3_5_56_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0907010106"},{"key":"e_1_3_5_57_2","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.antiviral.2007.06.007","article-title":"Construction and characterization of a stable subgenomic dengue virus type 2 replicon system for antiviral compound and siRNA testing","volume":"76","author":"Ng C. Y.","year":"2007","unstructured":"C. Y. Ng , Construction and characterization of a stable subgenomic dengue virus type 2 replicon system for antiviral compound and siRNA testing. Antiviral Res. 76, 222\u2013231 (2007).","journal-title":"Antiviral Res."},{"key":"e_1_3_5_58_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201606609"},{"key":"e_1_3_5_59_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00867-15"},{"key":"e_1_3_5_60_2","doi-asserted-by":"publisher","DOI":"10.1099\/vir.0.81844-0"},{"key":"e_1_3_5_61_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-50437-3"},{"key":"e_1_3_5_62_2","article-title":"\u201cElucidation of the mechanism-of-action of highly potent Dengue virus NS4B inhibitors JNJ-A07 and JNJ-1802,\u201d Doctoral dissertation, Department for Infectiology","author":"Kiemel D.","year":"2024","unstructured":"D. Kiemel, \u201cElucidation of the mechanism-of-action of highly potent Dengue virus NS4B inhibitors JNJ-A07 and JNJ-1802,\u201d Doctoral dissertation, Department for Infectiology, Ruprecht - Karls - University, Heidelberg, Germany (2024).","journal-title":"."},{"key":"e_1_3_5_63_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2421573122"},{"key":"e_1_3_5_64_2","doi-asserted-by":"publisher","DOI":"10.1080\/22221751.2020.1829994"},{"key":"e_1_3_5_65_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab1038"}],"updated-by":[{"DOI":"10.1073\/pnas.2606246123","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T00:00:00Z","timestamp":1773619200000}}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2426922122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T19:07:36Z","timestamp":1773688056000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2426922122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,28]]},"references-count":65,"journal-issue":{"issue":"13","published-print":{"date-parts":[[2025,4,1]]}},"alternative-id":["10.1073\/pnas.2426922122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2426922122","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.12.15.628546","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,28]]},"assertion":[{"value":"2024-12-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2426922122"}}