{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T11:04:16Z","timestamp":1784545456094,"version":"3.55.0"},"reference-count":75,"publisher":"Wiley","issue":"30","license":[{"start":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T00:00:00Z","timestamp":1779667200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T00:00:00Z","timestamp":1779667200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Angew Chem Int Ed"],"published-print":{"date-parts":[[2026,7,20]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Hydrophobic and aggregation\u2010prone proteins still present obstacles for protein chemical synthesis and engineering. The chemical synthesis of Interleukin\u201015 (IL\u201015) is a formidable challenge due to inherent sequence hydrophobicity and severe peptide aggregation, which impedes downstream protein engineering and chemical biology studies. Here, we report the first total synthesis of IL\u201015 using a versatile solubilizing strategy (RST\u20102.0), which enables the preparation and ligation of aggregation\u2010prone segments while being readily removable during folding. Remarkably, this strategy is fully compatible with glycopeptide synthesis, allowing for the synthesis of homogeneously N79\u2010glycosylated IL\u201015. The effectiveness of RST\u20102.0 was further demonstrated through the efficient synthesis of wild\u2010type and azide\u2010labeled Interleukin\u20102 (IL\u20102) analogs. Moreover, the bioactivity of IL\u201015 and IL\u20102 analogs was validated by CTLL\u20102 proliferation assays and microscale thermophoresis (MST). This work provides a\n                    <jats:italic>de novo<\/jats:italic>\n                    synthesis approach to elucidate the role of N\u2010glycosylation on IL\u201015\u2010mediated immune regulation and lays the foundation for developing next\u2010generation cancer immunotherapies based on synthetic IL\u201015 variants.\n                  <\/jats:p>","DOI":"10.1002\/anie.2586132","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T08:59:53Z","timestamp":1779699593000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Total Chemical Synthesis of Interleukin\u201015 and Interleukin\u20102: Taming Protein Hydrophobicity and Aggregation by a Versatile Solubilizing Strategy"],"prefix":"10.1002","volume":"65","author":[{"given":"Jingwen","family":"Zeng","sequence":"first","affiliation":[{"name":"Department of Chemistry State Key Laboratory of Synthetic Chemistry The University of Hong Kong  Hong Kong SAR P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Chemistry State Key Laboratory of Synthetic Chemistry The University of Hong Kong  Hong Kong SAR P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wang","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Chemistry State Key Laboratory of Synthetic Chemistry The University of Hong Kong  Hong Kong SAR P. R. China"},{"name":"Current address: School of Environmental and Chemical Engineering Wuyi University  Jiangmen 529020 P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongxiang","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Chemistry State Key Laboratory of Synthetic Chemistry The University of Hong Kong  Hong Kong SAR P. R. China"},{"name":"Current address: Zhongshan Institute For Drug Discovery Shanghai Institute of Materia Medica Chinese Academy of Sciences  Zhongshan 528400 P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5465-7727","authenticated-orcid":false,"given":"Xuechen","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Chemistry State Key Laboratory of Synthetic Chemistry The University of Hong Kong  Hong Kong SAR P. R. China"},{"name":"Laboratory For Marine Drugs and Bioproducts Qingdao Marine Science and Technology Center School of Medicine and Pharmacy Ocean University of China  Qingdao 266237 P. R. China"},{"name":"Shanghai\u2010Hong Kong Joint Laboratory in Chemical Synthesis Shanghai Institute of Organic Chemistry University of Chinese Academy of Sciences Chinese Academy of Sciences  Shanghai 200032 P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,25]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.8178155"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.11.4935"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2449"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri1901"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1158\/2326\u20106066.CIR\u201015\u20100009"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577\u2010022\u201000680\u2010w"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abo5409"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3156"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577\u2010018\u20100046\u2010y"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010018\u20100830\u20107"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.610789"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00868"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23137311"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M706150200"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni1492"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200501023"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2021.02.023"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.08.019"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1500678"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.0c08719"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202100543"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.4c01413"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.4c17873"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.25.022106.141702"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1039\/D2SC05660G"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1039\/D1SC06387A"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41557\u2010025\u201001896\u20108"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010020\u201014755\u20106"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010023\u201041115\u2010x"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.4c08049"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.4c00314"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.5c11459"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr800323s"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201501847"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.6b00515"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1039\/D0SC06001A"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.orglett.6b01442"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202504405"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.4c14247"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1039\/D3SC06032B"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja5018442"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.accounts.7b00277"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.accounts.8b00151"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.8b00712"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.9b12558"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202003652"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.0c07663"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chempr.2022.07.017"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.4c13464"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202502884"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.1c10091"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202317789"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010021\u201021209\u20100"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.7b00483"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/0040\u20104039(95)00667\u20102"},{"key":"e_1_2_8_57_1","doi-assert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