{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T05:27:57Z","timestamp":1791523677557,"version":"4.3.4"},"reference-count":83,"publisher":"Wiley","issue":"36","license":[{"start":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T00:00:00Z","timestamp":1751241600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T00:00:00Z","timestamp":1751241600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP23KJ0851"],"award-info":[{"award-number":["JP23KJ0851"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP21H05096"],"award-info":[{"award-number":["JP21H05096"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP21H05095"],"award-info":[{"award-number":["JP21H05095"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP21H05094"],"award-info":[{"award-number":["JP21H05094"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP23KK0105"],"award-info":[{"award-number":["JP23KK0105"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002241","name":"Japan Science and Technology Agency","doi-asserted-by":"publisher","award":["JPMJCR19S4"],"award-info":[{"award-number":["JPMJCR19S4"]}],"id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002241","name":"Japan Science and Technology Agency","doi-asserted-by":"publisher","award":["JPMJFR2122"],"award-info":[{"award-number":["JPMJFR2122"]}],"id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002241","name":"Japan Science and Technology Agency","doi-asserted-by":"publisher","award":["JPMJFR201F"],"award-info":[{"award-number":["JPMJFR201F"]}],"id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002241","name":"Japan Science and Technology Agency","doi-asserted-by":"publisher","award":["JPMJFR204W"],"award-info":[{"award-number":["JPMJFR204W"]}],"id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007684","name":"Asahi Glass Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007684","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018456","name":"Kanagawa Institute of Industrial Science and Technology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100018456","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Angew Chem Int Ed"],"published-print":{"date-parts":[[2025,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The stress\u2010responsive up\u2010regulation process is a sophisticated biological response to maintain cellular homeostasis. In intracellular anti\u2010oxidant systems, the expression level of oxidoreductases is up\u2010regulated under oxidative stress, mitigating oxidative damage on biomolecules and enhancing protein folding capacity. Herein, inspired by the biological system, we developed a synthetic folding promotor whose reactivity is up\u2010regulated under stress conditions. We conjugated two metal\u2010binding 1,4,7,11\u2010tetraazacyclotetradecane (cyclam) ligands and a redox\u2010active disulfide to obtain cyclam\u2010SS, whose reactivity can be enhanced under metal\u2010induced stress. Metal coordination increased the redox potential of cyclam\u2010SS, activating it as an oxidant. While Cu\n                    <jats:sup>II<\/jats:sup>\n                    ions severely hampered the oxidative folding of substrate polypeptides, cyclam\u2010SS exhibited bifunctional folding\u2010promoting properties, i) suppressing Cu\n                    <jats:sup>II<\/jats:sup>\n                    \u2010mediated misfolding and aggregation, and ii) harnessing Cu\n                    <jats:sup>II<\/jats:sup>\n                    to enhance oxidative folding. Cyclam\u2010SS was also useful for disulfide\u2010bond formation to promote oxidative folding of pharmaceutical and pathological proteins, as demonstrated with proinsulin and superoxide dismutase 1 (SOD1). Furthermore, cyclam\u2010SS protected cultured cells from copper\u2010induced stress. Thus, we demonstrated the induction of the stress\u2010responsive up\u2010regulation process by a bifunctional folding promotor controlling the folding status of biologically important proteins under metal\u2010induced stress. The strategy of \u201cstress\u2010responsive up\u2010regulation\u201d could aid the development of novel synthetic materials for treating intracellular stress and related disorders.\n                  <\/jats:p>","DOI":"10.1002\/anie.202502187","type":"journal-article","created":{"date-parts":[[2025,7,13]],"date-time":"2025-07-13T12:41:24Z","timestamp":1752410484000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Metal\u2010Responsive Up\u2010Regulation of Bifunctional Disulfides for Suppressing Protein Misfolding and Promoting Oxidative Folding"],"prefix":"10.1002","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3572-7384","authenticated-orcid":false,"given":"Keita","family":"Mori","sequence":"first","affiliation":[{"name":"Department of Applied Chemistry Graduate School of Engineering Tokyo University of Agriculture and Technology 2\u201024\u201016 Naka\u2010cho  Koganei Tokyo 184\u20138588 Japan"},{"name":"Department of Chemistry Massachusetts Institute of Technology 77 Massachusetts Avenue  Cambridge MA 02139 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsubura","family":"Kuramochi","sequence":"additional","affiliation":[{"name":"Frontier Research Institute for Interdisciplinary Sciences Tohoku University 6\u20103 Aramaki\u2010Aza\u2010Aoba  Aoba\u2010ku Sendai Miyagi 980\u20138578 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motonori","family":"Matsusaki","sequence":"additional","affiliation":[{"name":"Institute of Advanced Medical Sciences Tokushima University 3\u201018\u20105 Kuramoto\u2010cho  Tokushima 770\u20138503 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Hashiguchi","sequence":"additional","affiliation":[{"name":"Department of Chemistry Keio University 3\u201014\u20101 Hiyoshi  Kohoku Yokohama Kanagawa 223\u20138522 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Okumura","sequence":"additional","affiliation":[{"name":"Frontier Research Institute for Interdisciplinary Sciences Tohoku University 6\u20103 Aramaki\u2010Aza\u2010Aoba  Aoba\u2010ku Sendai Miyagi 980\u20138578 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohide","family":"Saio","sequence":"additional","affiliation":[{"name":"Institute of Advanced Medical Sciences Tokushima University 3\u201018\u20105 Kuramoto\u2010cho  Tokushima 770\u20138503 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiaki","family":"Furukawa","sequence":"additional","affiliation":[{"name":"Department of Chemistry Keio University 3\u201014\u20101 Hiyoshi  Kohoku Yokohama Kanagawa 223\u20138522 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenta","family":"Arai","sequence":"additional","affiliation":[{"name":"Department of Chemistry School of Science Tokai University 4\u20101\u20101 Kitakaname  Hiratsuka Kanagawa 259\u20131292 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6744-048X","authenticated-orcid":false,"given":"Takahiro","family":"Muraoka","sequence":"additional","affiliation":[{"name":"Department of Applied Chemistry Graduate School of Engineering Tokyo University of Agriculture and Technology 2\u201024\u201016 Naka\u2010cho  Koganei Tokyo 184\u20138588 Japan"},{"name":"Kanagawa Institute of Industrial Science and Technology 3\u20102\u20101 Sakato  Takatsu\u2010ku Kawasaki Kanagawa 213\u20100012 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,6,30]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-018-0068-0"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-021-00233-1"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202000451"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox12051078"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/jb\/mvp166"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1209038"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3270"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2015.00080"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.8b00672"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.2c00879"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1039\/9781849739979"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-94-007-5561-1"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx989"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1039\/c000429d"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.11.028"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1913"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08300"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro.2017.15"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom4010252"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.accounts.9b00248"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr400327t"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinorgbio.2011.11.024"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr400479b"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abf0529"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-022-01229-y"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1039\/D3CB00145H"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1021\/ic4031377"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.5b11561"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr040410w"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom10020195"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-018-0018-3"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2012.12.021"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom9070269"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1039\/D0QI00791A"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.181.4096.223"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1021\/ar000063m"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules26010195"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1039\/D3SC05781J"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-019-0268-8"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21249351"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja016938p"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1039\/C4OB01738B"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi700124p"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.201700624"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2011.08039.x"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja211931f"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1039\/C8CC08657E"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1002\/asia.202000682"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1039\/D3SC01540H"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1039\/C5CC01261A"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1039\/c3cp54946a"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0020-1693(00)80594-0"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1039\/C7DT00750G"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1039\/dt9770002269"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1021\/ic00162a038"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo00067a060"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo00124a037"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1716783"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1039\/D4SC02123A"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1101\/2024.03.04.583432"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.79.8.2470"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00061a028"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi9725327"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/27.18.3696"},{"key":"e_1_2_8_65_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.44532"},{"key":"e_1_2_8_66_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.60970"},{"key":"e_1_2_8_67_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsbiomedchemau.1c00054"},{"key":"e_1_2_8_68_1","doi-asserted-by":"publisher","DOI":"10.1039\/D4CC01712A"},{"key":"e_1_2_8_69_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00244-6"},{"key":"e_1_2_8_70_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11910-009-0030-9"},{"key":"e_1_2_8_71_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2006.12.005"},{"key":"e_1_2_8_72_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M500482200"},{"key":"e_1_2_8_73_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.3094"},{"key":"e_1_2_8_74_1","doi-asserted-by":"publisher","DOI":"10.1039\/C8MT00182K"},{"key":"e_1_2_8_75_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.bioconjchem.0c00133"},{"key":"e_1_2_8_76_1","doi-asserted-by":"publisher","DOI":"10.1111\/ene.12348"},{"key":"e_1_2_8_77_1","first-page":"199","volume":"3","author":"Miller A. L.","year":"1998","journal-title":"Altern. Med. Rev."},{"key":"e_1_2_8_78_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinorgbio.2014.04.011"},{"key":"e_1_2_8_79_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-9861(59)90090-6"},{"key":"e_1_2_8_80_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja051306e"},{"key":"e_1_2_8_81_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00197809"},{"key":"e_1_2_8_82_1","doi-asserted-by":"publisher","DOI":"10.1038\/227680a0"},{"key":"e_1_2_8_83_1","doi-asserted-by":"publisher","DOI":"10.1101\/2024.07.30.605722"}],"container-title":["Angewandte Chemie International Edition"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.202502187","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/anie.202502187","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.202502187","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.202502187","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T16:24:09Z","timestamp":1784305449000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/anie.202502187"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,30]]},"references-count":83,"journal-issue":{"issue":"36","published-print":{"date-parts":[[2025,9,1]]}},"alternative-id":["10.1002\/anie.202502187"],"URL":"https:\/\/doi.org\/10.1002\/anie.202502187","archive":["Portico"],"relation":{},"ISSN":["1433-7851","1521-3773"],"issn-type":[{"value":"1433-7851","type":"print"},{"value":"1521-3773","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,30]]},"assertion":[{"value":"2025-01-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e202502187"}}