{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T14:27:16Z","timestamp":1789050436156,"version":"build-2803163510"},"reference-count":33,"publisher":"Wiley","issue":"26","license":[{"start":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T00:00:00Z","timestamp":1743984000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T00:00:00Z","timestamp":1743984000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22307133"],"award-info":[{"award-number":["22307133"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22277130"],"award-info":[{"award-number":["22277130"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32471306"],"award-info":[{"award-number":["32471306"]}],"id":[{"id":"10.13039\/501100001809","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":[[2025,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Monkeypox virus (MPXV), an orthopoxvirus that has long been endemic in Africa, has posed a significant global health threat since 2022. The I7L protease, a highly conserved cysteine proteinase essential for orthopoxvirus replication, represents a promising target for broad\u2010spectrum antiviral drug development. Here, the first crystal structure of MPXV I7L protease is reported, revealing its unique dimeric form and different conformations of a cap region nearby the active site. Molecular dynamics\u00a0simulations and AlphaFold3 prediction of protease\u2010substrate structures both suggest that this highly flexible cap acts as a conformational switch, regulating the substrate access to the active site. Additionally, the structural basis of substrate recognition and the catalytic mechanism of the protease are elucidated, mapping determinants of substrate specificity. These insights enable us to design covalent inhibitors to mimic the natural substrates and develop a fluorescence resonance energy transfer (FRET)\u2010based protease assay to effectively assess the inhibitory activity, leading to the discovery of first\u2010in\u2010class inhibitors of MPXV I7L protease with nanomolar potency. Therefore, this work provides a comprehensive understanding of the MPXV I7L protease's structure, dynamics, and function, and presents an example of successful rational design of covalent peptidomimetic inhibitors, serving as a good starting point for drug development against MPXV.<\/jats:p>","DOI":"10.1002\/advs.202501625","type":"journal-article","created":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T18:00:25Z","timestamp":1744048825000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Dynamic Cap\u2010Mediated Substrate Access and Potent Inhibitor Design of Monkeypox Virus I7L Protease"],"prefix":"10.1002","volume":"12","author":[{"given":"Haixia","family":"Su","sequence":"first","affiliation":[{"name":"State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai 201203 China"},{"name":"University of Chinese Academy of Sciences  Beijing 100049 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoqing","family":"Wu","sequence":"additional","affiliation":[{"name":"Lingang Laboratory  Shanghai 200031 China"},{"name":"School of Physical Science and Technology ShanghaiTech University  Shanghai 201210 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muya","family":"Xiong","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study University of Chinese Academy of Sciences  Hangzhou 310024 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhang","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica Nanjing University of Chinese Medicine  Nanjing 210023 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyuan","family":"Cao","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega\u2010Science Chinese Academy of Sciences  Wuhan 430064 China"},{"name":"Hubei Jiangxia Laboratory  Wuhan 430200 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyuan","family":"You","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai 201203 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingchun","family":"Xiang","sequence":"additional","affiliation":[{"name":"Hubei Jiangxia Laboratory  Wuhan 430200 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianqing","family":"Nie","sequence":"additional","affiliation":[{"name":"Lingang Laboratory  Shanghai 200031 China"},{"name":"School of Physical Science and Technology ShanghaiTech University  Shanghai 201210 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minjun","family":"Li","sequence":"additional","affiliation":[{"name":"Shanghai Synchrotron Radiation Facility, Shanghai Advanced Research Institute Chinese Academy of Sciences  Shanghai 201204 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gengfu","family":"Xiao","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega\u2010Science Chinese Academy of Sciences  Wuhan 430064 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leike","family":"Zhang","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega\u2010Science Chinese Academy of Sciences  Wuhan 430064 China"},{"name":"Hubei Jiangxia Laboratory  Wuhan 430200 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Shao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai 201203 China"},{"name":"University of Chinese Academy of Sciences  Beijing 100049 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1581-6155","authenticated-orcid":false,"given":"Yechun","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai 201203 China"},{"name":"University of Chinese Academy of Sciences  Beijing 100049 China"},{"name":"School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study University of Chinese Academy of Sciences  Hangzhou 310024 China"},{"name":"School of Chinese Materia Medica Nanjing University of Chinese Medicine  Nanjing 210023 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,4,7]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)02075-X"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-024-01690-1"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-03130-3"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c00069"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.12.6335-6343.2004"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.76.17.8973-8976.2002"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.77.20.11279-11283.2003"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.69.11.7072-7086.1995"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/ar700109k"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/ml9000276"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.50.5.1813-1822.2006"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003495-200363080-00004"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c00117"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-18233-x"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-42102-y"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abl4784"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.67.1.1"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro3046"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/med.21783"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07487-w"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.22.12147-12156.2004"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1186\/1743-422X-2-63"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(00)80326-3"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jctc.5b00436"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi036022q"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1039\/D3SC00166K"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.4c01594"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c00058"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1021\/acscatal.0c03420"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1039\/D0SC02823A"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.388678"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2024.21091"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsb1196-946"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202501625","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/advs.202501625","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202501625","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T16:22:37Z","timestamp":1775751757000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.202501625"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,7]]},"references-count":33,"journal-issue":{"issue":"26","published-print":{"date-parts":[[2025,7]]}},"alternative-id":["10.1002\/advs.202501625"],"URL":"https:\/\/doi.org\/10.1002\/advs.202501625","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,7]]},"assertion":[{"value":"2025-01-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"2501625"}}