{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T15:08:08Z","timestamp":1790003288993,"version":"4.0.1"},"reference-count":66,"publisher":"Wiley","issue":"39","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["EXC 2008\u2013390540038"],"award-info":[{"award-number":["EXC 2008\u2013390540038"]}],"id":[{"id":"10.13039\/501100001659","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":[[2026,9,21]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Engineering immune\u2010silent, catalytically self\u2010sufficient antiviral restriction factor enzymes (iCAREs) provides a proof\u2010of\u2010concept for developing autonomous enzymes for future antiviral applications. To rationally design these enzymes, we sought to identify and engineer components of the intrinsic immune system. Here, we identified the endoplasmic reticulum (ER)\u2010anchored cytochrome b5 reductase 3 (CYB5R3) as a putative electron donor to the ER\u2010anchored and interferon\u2010stimulated antiviral radical S\u2010adenosylmethionine (SAM)\u2010dependent nucleotide dehydratase (SAND), or RSAD2 (viperin) in humans. We demonstrate that their functional partnership depends on co\u2010localisation. We obtained insights into the structure of the RSAD2:CYB5R3 complex and, using mutagenesis, identified the structural elements required for electron transfer. Based on this discovery, we engineered iCAREs that autonomously generate an antiviral nucleotide analogue to chain\u2010terminate viral RNA polymerase activity. Because iCAREs are self\u2010sufficient and do not require recruitment of endogenous redox partners, they are predicted to avoid interference with numerous biological processes associated with single\u2010domain redox partners such as CYB5R3, including electron delivery to the oncogenic enzyme stearoyl\u2010CoA desaturase (SCD1). This work solves a long\u2010standing question of why ER localisation is critical for RSAD2 activity, resolves a key mechanistic question in radical\u2010SAM enzymology, and establishes a general strategy to engineer self\u2010sufficient radical\u2010SAM enzymes for biotechnological applications.<\/jats:p>","DOI":"10.1002\/anie.5423408","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T13:32:13Z","timestamp":1784640733000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Discovery of an Antiviral Electron Transfer Process to Create Catalytically Self\u2010Sufficient Viral Restriction Factors"],"prefix":"10.1002","volume":"65","author":[{"given":"Mengdi","family":"Wu","sequence":"first","affiliation":[{"name":"Institute of Pharmaceutical Science King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2203-9139","authenticated-orcid":false,"given":"Nghi Thao","family":"Hoang","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science King's College London  London UK"},{"name":"Department of Pharmacy Da Nang University of Medical Technology and Pharmacy  Da Nang Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Grifagni","sequence":"additional","affiliation":[{"name":"Magnetic Resonance Center and Department of Chemistry University of Florence  Sesto Fiorentino Tuscany Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8130-6846","authenticated-orcid":false,"given":"Meritxell","family":"Wu\u2010Lu","sequence":"additional","affiliation":[{"name":"Department of Chemistry Technical University of Berlin  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"Sheng","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9332-5094","authenticated-orcid":false,"given":"Theo","family":"Situmorang","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei\u2010Hsin","family":"Tai","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1390-9082","authenticated-orcid":false,"given":"Astrid","family":"Maluta","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Hakil","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca","family":"Susini","sequence":"additional","affiliation":[{"name":"Magnetic Resonance Center and Department of Chemistry University of Florence  Sesto Fiorentino Tuscany Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Florance","sequence":"additional","affiliation":[{"name":"Institution: Agilent Technologies  Cheadle UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6342-2022","authenticated-orcid":false,"given":"Peter\u2010Leon","family":"Hagedoorn","sequence":"additional","affiliation":[{"name":"Department of Biotechnology Delft University of Technology  Delft the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John Mark","family":"Sutton","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science King's College London  London UK"},{"name":"UK Health Security Agency  Salisbury UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7497-5631","authenticated-orcid":false,"given":"Maria\u2010Andrea","family":"Mroginski","sequence":"additional","affiliation":[{"name":"Department of Chemistry Technical University of Berlin  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2376-3321","authenticated-orcid":false,"given":"Simone","family":"Ciofi\u2010Baffoni","sequence":"additional","affiliation":[{"name":"Magnetic Resonance Center and Department of Chemistry University of Florence  Sesto Fiorentino Tuscany Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6628-944X","authenticated-orcid":false,"given":"Kourosh H.","family":"Ebrahimi","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200704630"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200351434"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201609758"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2018.11.021"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.2c00336"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt744"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202002861"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adi5554"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.202300133"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41929\u2010020\u20100448\u20107"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2018.09.001"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2022.1032220"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41579\u2010024\u201001017\u20101"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1039\/C7MT00341B"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.011593298"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M807261200"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0911679106"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2010.02.041"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.12.032"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/1873\u20103468.13778"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.15625"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41557\u2010021\u201000882\u20100"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep30529"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010virology\u2010011720\u2010095930"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2013.10.019"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41559\u2010024\u201002463\u2010z"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010018\u20100238\u20104"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.201900776"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA119.011526"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.9b00741"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2023.105058"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2007.06.009"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24542"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010018\u201026516\u2010z"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010020\u20102762\u20102"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1039\/D3CC00638G"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.102654"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.70936"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.5b00210"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioadv\/vbac059"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.21203\/rs.3.rs\u20107603489\/v1"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1021\/ar020084b"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja9064574"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2013.07.009"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202010006"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742\u20104658.2011.08062.x"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432\u20101033.1992.tb16702.x"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.3390\/magnetochemistry6040046"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00775\u2010018\u20101552\u2010x"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10858\u2010013\u20109741\u2010y"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0167\u20104838(97)00146\u20105"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1107\/S205979831900754X"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1705402114"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.3c02719"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1002\/celc.201801256"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12951\u2010023\u201002044\u20105"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2022.07.010"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.582999"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coviro.2016.02.009"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003497"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2023.102338"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers11070948"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046\u2010021\u201002067\u20106"},{"key":"e_1_2_8_65_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276\u2010024\u201001155\u20109"},{"key":"e_1_2_8_66_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09138"},{"key":"e_1_2_8_67_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.3265"}],"container-title":["Angewandte Chemie International Edition"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.5423408","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/anie.5423408","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.5423408","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T14:45:33Z","timestamp":1790001933000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/anie.5423408"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,21]]},"references-count":66,"journal-issue":{"issue":"39","published-print":{"date-parts":[[2026,9,21]]}},"alternative-id":["10.1002\/anie.5423408"],"URL":"https:\/\/doi.org\/10.1002\/anie.5423408","archive":["Portico"],"relation":{},"ISSN":["1433-7851","1521-3773"],"issn-type":[{"value":"1433-7851","type":"print"},{"value":"1521-3773","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,21]]},"assertion":[{"value":"2025-12-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-19","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-21","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e5423408"}}