{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T16:42:12Z","timestamp":1792255332495,"version":"4.4.0"},"reference-count":41,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T00:00:00Z","timestamp":1792195200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T00:00:00Z","timestamp":1792195200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["ERC\u20102016\u2010STG\u2010716878"],"award-info":[{"award-number":["ERC\u20102016\u2010STG\u2010716878"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["ERC\u2010POC\u20102023"],"award-info":[{"award-number":["ERC\u2010POC\u20102023"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["MSCA\u20102019\u2010IF\u2010898128"],"award-info":[{"award-number":["MSCA\u20102019\u2010IF\u2010898128"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Angew Chem Int Ed"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The saponin natural product QS\u201021 is a potent immunological adjuvant used in human vaccines to enhance the immune response but suffers from scarcity, instability, and dose\u2010limiting toxicity, precluding its advancement as a stand\u2010alone adjuvant. Further, putative cellular receptor(s) and its molecular mechanisms of action are unknown, which has prevented the rational design of saponin adjuvants, emphasizing the need for discovering these receptors and elucidating mechanisms. Herein, we have developed novel saponin photoaffinity probes for molecular target identification, merging synthetic chemistry, photoaffinity labeling, and chemical proteomics. One of these potent adjuvants generated superior antibody responses to\u00a0QS\u201021 with less toxicity and enabled identification of Cathepsin D (CatD) as the selective receptor driving saponin adjuvant effects. Binding to surface\u2010exposed CatD, lipid raft interactions, and lysosomal acidification were shown to be key for CatD\u2010mediated saponin\u2010induced immune activation, whereas neither photocrosslinking nor apparent binding was observed in comparative experiments with other lysosomal cathepsins, confirming the specificity of the interaction. These studies highlight the promise of this saponin probe as a potent vaccine adjuvant, unveiling CatD as the molecular target. This breakthrough sets the stage for elucidating the precise mechanisms of saponin immunopotentiation, facilitating rational adjuvant design and development of optimized adjuvant\u2013antigen combinations for future vaccines.<\/jats:p>","DOI":"10.1002\/anie.5055772","type":"journal-article","created":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T16:00:46Z","timestamp":1792252846000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Development of a Potent QS\u201021\u2010Derived Adjuvant Photoaffinity Probe: Identification of Cathepsin D as the Molecular Receptor"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8241-7253","authenticated-orcid":false,"given":"Abhijit","family":"Saha","sequence":"first","affiliation":[{"name":"Chemical Immunology Laboratory Center for Cooperative Research in Biosciences (CIC bioGUNE) Basque Research and Technology Alliance (BRTA)  Derio Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0136-8643","authenticated-orcid":false,"given":"Alba","family":"Mosteiro\u2010Couso","sequence":"additional","affiliation":[{"name":"Chemical Immunology Laboratory Center for Cooperative Research in Biosciences (CIC bioGUNE) Basque Research and Technology Alliance (BRTA)  Derio Spain"},{"name":"Inflammation and Macrophage Plasticity Laboratory Center for Cooperative Research in Biosciences (CIC bioGUNE) Basque Research and Technology Alliance (BRTA)  Derio Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6963-0102","authenticated-orcid":false,"given":"Adri\u00e1n","family":"Plata","sequence":"additional","affiliation":[{"name":"Chemical Immunology Laboratory Center for Cooperative Research in Biosciences (CIC bioGUNE) Basque Research and Technology Alliance (BRTA)  Derio Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0861-1378","authenticated-orcid":false,"given":"Carlo","family":"Pifferi","sequence":"additional","affiliation":[{"name":"Chemical Immunology Laboratory Center for Cooperative Research in Biosciences (CIC bioGUNE) Basque Research and Technology Alliance (BRTA)  Derio Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6361-0357","authenticated-orcid":false,"given":"Priscila","family":"Tonon\u2010Baschirotto","sequence":"additional","affiliation":[{"name":"Chemical Immunology Laboratory Center for Cooperative Research in Biosciences (CIC bioGUNE) Basque Research and Technology Alliance (BRTA)  Derio Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2870-3344","authenticated-orcid":false,"given":"Iker","family":"Oyenarte","sequence":"additional","affiliation":[{"name":"Cancer Glycoimmunology Laboratory Center for Cooperative Research in Biosciences (CIC bioGUNE) Basque Research and Technology Alliance (BRTA)  Derio Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5076-2105","authenticated-orcid":false,"given":"June","family":"Ere\u00f1o\u2010Orbea","sequence":"additional","affiliation":[{"name":"Cancer Glycoimmunology Laboratory Center for Cooperative Research in Biosciences (CIC bioGUNE) Basque Research and Technology Alliance (BRTA)  Derio Spain"},{"name":"Ikerbasque, Basque Foundation for Science  Bilbao Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9115-3202","authenticated-orcid":false,"given":"Mikel","family":"Azkargorta","sequence":"additional","affiliation":[{"name":"Proteomics Platform Center for Cooperative Research in Biosciences (CIC bioGUNE) Basque Research and Technology Alliance (BRTA)  Derio Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8839-5438","authenticated-orcid":false,"given":"F\u00e9lix","family":"Elortza","sequence":"additional","affiliation":[{"name":"Proteomics Platform Center for Cooperative Research in Biosciences (CIC bioGUNE) Basque Research and Technology Alliance (BRTA)  Derio Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2061-7182","authenticated-orcid":false,"given":"Juan","family":"Anguita","sequence":"additional","affiliation":[{"name":"Inflammation and Macrophage Plasticity Laboratory Center for Cooperative Research in Biosciences (CIC bioGUNE) Basque Research and Technology Alliance (BRTA)  Derio Spain"},{"name":"Ikerbasque, Basque Foundation for Science  Bilbao Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1680-0059","authenticated-orcid":false,"given":"Alberto","family":"Fern\u00e1ndez\u2010Tejada","sequence":"additional","affiliation":[{"name":"Chemical Immunology Laboratory Center for Cooperative Research in Biosciences (CIC bioGUNE) Basque Research and Technology Alliance (BRTA)  Derio Spain"},{"name":"Ikerbasque, Basque Foundation for Science  Bilbao Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,17]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(24)00850\u2010X"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1080\/21645515.2021.1977057"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3409"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2019.152905"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchem.1963"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.146.2.431"},{"key":"e_1_2_10_8_1","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.smim.2018.05.001","article-title":"Correlates of Adjuvanticity: A Review on Adjuvants in Licensed Vaccines","volume":"39","author":"Del Giudice G.","year":"2018","journal-title":"Seminars in Immunology"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1080\/21645515.2023.2189885"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2017.06.002"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.865507"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.accounts.6b00242"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1515\/pac\u20102016\u20101213"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1039\/C5SC02978C"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/chem.202004705"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1039\/D1CC04459A"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1039\/C9CC07781B"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja305121q"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41570\u2010020\u201000244\u20103"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1400948"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/978\u20101\u20104939\u20106445\u20101_4"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2016.00663"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.683011"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1005562"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.64.11.10"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20\u201018\u201006898.2000"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460\u20102075.1995.tb00029.x"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010022\u201015805\u20103"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5577\u201006.2007"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9071679"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.7136"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2004.01.021"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep39475"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2018.03.005"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1359\u20106446(03)02864\u20102"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1002421"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.12.007"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.551"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2017.16"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1174621"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41556\u2010025\u201001616\u2010x"}],"container-title":["Angewandte Chemie International Edition"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.5055772","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/anie.5055772","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.5055772","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T16:00:48Z","timestamp":1792252848000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/anie.5055772"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,17]]},"references-count":41,"alternative-id":["10.1002\/anie.5055772"],"URL":"https:\/\/doi.org\/10.1002\/anie.5055772","archive":["Portico"],"relation":{},"ISSN":["1433-7851","1521-3773"],"issn-type":[{"value":"1433-7851","type":"print"},{"value":"1521-3773","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,17]]},"assertion":[{"value":"2026-06-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e5055772"}}