{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T02:29:19Z","timestamp":1790994559989,"version":"4.1.0"},"reference-count":74,"publisher":"Wiley","issue":"42","license":[{"start":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T00:00:00Z","timestamp":1757894400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR2024QH201"],"award-info":[{"award-number":["ZR2024QH201"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012165","name":"Key Technologies Research and Development Program","doi-asserted-by":"publisher","award":["2023YFC2606500"],"award-info":[{"award-number":["2023YFC2606500"]}],"id":[{"id":"10.13039\/501100012165","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014440","name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","doi-asserted-by":"publisher","award":["PID2022\u2010136307OB\u2010C22\/AEI\/10.13039\/501100011033"],"award-info":[{"award-number":["PID2022\u2010136307OB\u2010C22\/AEI\/10.13039\/501100011033"]}],"id":[{"id":"10.13039\/100014440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Herpes simplex viruses (HSV\u20101 and HSV\u20102) are highly prevalent and contagious, causing lifelong infections that cannot be eradicated with current therapies. Acyclovir and other viral DNA polymerase inhibitors are effective antiviral agents for treating HSV infections. However, despite the recent approval of pritelivir and amenamevir (helicase\u2013primase complex inhibitors), drug resistance is still a major threat to therapeutic success. This research focuses on developing new antiviral strategies against HSV\u20101 by targeting the pUL15 endonuclease, a component of the viral packaging motor\/terminase complex, using substituted polycyclic pyridones derived from baloxavir acid. Several compounds display low micromolar IC\n                    <jats:sub>50<\/jats:sub>\n                    values in enzymatic assays. Among them, the prioritized compound,\n                    <jats:bold>LN\u20107<\/jats:bold>\n                    , shows a 50% effective concentration (EC\n                    <jats:sub>50<\/jats:sub>\n                    ) of 2.8\u00a0\u00b1\u00a01.1\u00a0\u00b5\n                    <jats:sc>m<\/jats:sc>\n                    in antiviral assays and favorable pharmacokinetic properties in rats.\n                    <jats:bold>LN\u20107<\/jats:bold>\n                    demonstrates antiviral efficacy in infected mice, while exhibiting fewer clinical signs compared to controls. Overall,\n                    <jats:bold>LN\u20107<\/jats:bold>\n                    emerges as a promising lead for treating herpesvirus infections and is therefore a first\u2010in\u2010class drug candidate targeting HSV genome packaging.\n                  <\/jats:p>","DOI":"10.1002\/advs.202508006","type":"journal-article","created":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T09:05:39Z","timestamp":1757927139000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Discovery of a Baloxavir\u2010Inspired Endonuclease Inhibitor That Prevents Herpes Simplex Virus 1 Replication in Cell Culture and In Vivo"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0600-4152","authenticated-orcid":false,"given":"Sabina","family":"Andreu","sequence":"first","affiliation":[{"name":"Centro de Biolog\u00eda Molecular \u201cSevero Ochoa \u201d Consejo Superior de Investigaciones Cient\u00edficas and Universidad Aut\u00f3noma de Madrid  c\/ Nicol\u00e1s Cabrera 1, Campus de Cantoblanco\u2010UAM Madrid 28049 Spain"},{"name":"Department of Molecular Biology Universidad Aut\u00f3noma de Madrid  c\/ Darwin, 2 Cantoblanco Madrid 28049 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9770-9459","authenticated-orcid":false,"given":"Kai","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Key Laboratory of Chemical Biology Ministry of Education School of Pharmaceutical Sciences Cheeloo College of Medicine Shandong University  Jinan 250012 P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahui","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Key Laboratory of Chemical Biology Ministry of Education School of Pharmaceutical Sciences Cheeloo College of Medicine Shandong University  Jinan 250012 P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Pino\u2010Peco","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular \u201cSevero Ochoa \u201d Consejo Superior de Investigaciones Cient\u00edficas and Universidad Aut\u00f3noma de Madrid  c\/ Nicol\u00e1s Cabrera 1, Campus de Cantoblanco\u2010UAM Madrid 28049 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nerea","family":"L\u00f3pez\u2010Carrobles","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular \u201cSevero Ochoa \u201d Consejo Superior de Investigaciones Cient\u00edficas and Universidad Aut\u00f3noma de Madrid  c\/ Nicol\u00e1s Cabrera 1, Campus de Cantoblanco\u2010UAM Madrid 28049 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4415-6483","authenticated-orcid":false,"given":"Raquel","family":"Bello\u2010Morales","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology Universidad Aut\u00f3noma de Madrid  c\/ Darwin, 2 Cantoblanco Madrid 28049 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3532-4760","authenticated-orcid":false,"given":"Daniel","family":"Galdo\u2010Torres","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology Universidad Aut\u00f3noma de Madrid  c\/ Darwin, 2 Cantoblanco Madrid 28049 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Key Laboratory of Chemical Biology Ministry of Education School of Pharmaceutical Sciences Cheeloo College of Medicine Shandong University  Jinan 250012 P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3071-4878","authenticated-orcid":false,"given":"Federico","family":"Gago","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences Universidad de Alcal\u00e1  Alcal\u00e1 de Henares Madrid 28805 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2817-5956","authenticated-orcid":false,"given":"Jos\u00e9 Antonio","family":"L\u00f3pez\u2010Guerrero","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular \u201cSevero Ochoa \u201d Consejo Superior de Investigaciones Cient\u00edficas and Universidad Aut\u00f3noma de Madrid  c\/ Nicol\u00e1s Cabrera 1, Campus de Cantoblanco\u2010UAM Madrid 28049 Spain"},{"name":"Department of Molecular Biology Universidad Aut\u00f3noma de Madrid  c\/ Darwin, 2 Cantoblanco Madrid 28049 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7302-2214","authenticated-orcid":false,"given":"Xinyong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Key Laboratory of Chemical Biology Ministry of Education School of Pharmaceutical Sciences Cheeloo College of Medicine Shandong University  Jinan 250012 P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9675-6026","authenticated-orcid":false,"given":"Peng","family":"Zhan","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Key Laboratory of Chemical Biology Ministry of Education School of Pharmaceutical Sciences Cheeloo College of Medicine Shandong University  Jinan 250012 P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1251-6640","authenticated-orcid":false,"given":"Luis","family":"Men\u00e9ndez\u2010Arias","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular \u201cSevero Ochoa \u201d Consejo Superior de Investigaciones Cient\u00edficas and Universidad Aut\u00f3noma de Madrid  c\/ Nicol\u00e1s Cabrera 1, Campus de Cantoblanco\u2010UAM Madrid 28049 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,15]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.2471\/BLT.19.237149"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjgh-2019-001875"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2018.07.006"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003495-200969020-00002"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-815422-9.00004-8"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.enz.2021.07.003"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1086\/590668"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-981-16-0267-2_1"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-3542(98)00048-5"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.46.8.2365-2372.2002"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.05265-11"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01794-13"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01955-12"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13238-020-00710-0"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00311-13"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1007144107"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.8b01472"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0033583510000181"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkt1414"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-021-00586-9"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2019.12.006"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.05.044"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.709139"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1039\/C4MD00055B"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gki268"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2013.06.007"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.101790"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.03875-14"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02675-15"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.03226-21"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1039\/D2RA06749H"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.5b01254"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01318-14"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00994-18"},{"key":"e_1_2_9_35_1","volume":"62","author":"Miller J. T.","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c01280"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.8b00254"},{"key":"e_1_2_9_38_1","unstructured":"K.Morimoto M.Kawai T.Akiyama H.Mikamiyama Y.Taoda K.Tomita N.Suzuki K.Takaya M.Mikamiyama C.Kageyama WO2010147068A1 2010."},{"key":"e_1_2_9_39_1","unstructured":"M.Kawai T.Akiyama H.Mikamiyama Y.Taoda K.Tomita N.Suzuki K.Anan C.Kageyama M.Miyagawa WO2012039414A1 2012."},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coviro.2019.01.006"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2019.104545"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a038687"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.9.7563-7568.1998"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3006667"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-1947"},{"key":"e_1_2_9_46_1","unstructured":"M.Kawai K.Tomita T.Akiyama A.Okano M.Miyagawa Jpn. Tokkyo Koho JP5971830 2016."},{"key":"e_1_2_9_47_1","unstructured":"T.Shishido T.Noshi A.Yamamoto M.Kitano PCT Int. Appl. 201803246 2017."},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.6b01227"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2018.10.008"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2018.03026"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.3201\/eid2510.190607"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkaa337"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2206104119"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2024.105890"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature07745"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature07720"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-27890-4"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.100486"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.2174\/1386207317666140122101631"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01380-17"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1009460"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.virusres.2020.197896"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(81)90346-9"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2018.09.004"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac387"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03819-2"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw395"},{"key":"e_1_2_9_68_1","doi-asserted-by":"publisher","DOI":"10.3390\/cryst12040550"},{"key":"e_1_2_9_69_1","doi-asserted-by":"publisher","DOI":"10.1002\/1096-987X(200009)21:12<1049::AID-JCC3>3.0.CO;2-F"},{"key":"e_1_2_9_70_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.3359469"},{"key":"e_1_2_9_71_1","unstructured":"M. J.Frisch G. W.Trucks G. E.Schlegel M. A. R.Scuseria J. R.Cheeseman G.Scalmani V.Barone G. A.Petersson H.Nakatsuji X.Li M.Caricato A.Marenich J.Bloino B. G.Janesko R.Gomperts B.Mennucci H. P.Hratchian J. V.Ortiz A. F.Izmaylov J. L.Sonnenberg D.Williams\u2010Young F.Ding F.Lipparini F.Egidi J.Goings B.Peng A.Petrone T.Henderson D.Ranasinghe V. G.Zakrzewski et\u00a0al. Gaussian Inc. Wallingford CT2016 https:\/\/gaussian.com\/g09citation\/."},{"key":"e_1_2_9_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2009.09.016"},{"key":"e_1_2_9_73_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv1018"},{"key":"e_1_2_9_74_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.3c00536"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202508006","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T11:30:03Z","timestamp":1763119803000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.202508006"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,15]]},"references-count":74,"journal-issue":{"issue":"42","published-print":{"date-parts":[[2025,11]]}},"alternative-id":["10.1002\/advs.202508006"],"URL":"https:\/\/doi.org\/10.1002\/advs.202508006","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,15]]},"assertion":[{"value":"2025-05-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e08006"}}