{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T10:17:03Z","timestamp":1787912223078,"version":"build-2784847793"},"reference-count":44,"publisher":"Wiley","issue":"48","license":[{"start":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T00:00:00Z","timestamp":1780099200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T00:00:00Z","timestamp":1780099200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Immune checkpoint therapies have transformed immunotherapy but remain dominated by biologic agents characterized by prolonged receptor occupancy and limited pharmacologic controllability. Although multiple classes of immunomodulatory therapeutics exist, synthetic modalities capable of directly targeting extracellular immune checkpoint protein\u2013protein interaction interfaces while enabling controllable immune modulation remain comparatively underexplored. Here, we report an AI\u2010guided strategy for discovering cyclic peptide antagonists of the costimulatory receptor CD28. The lead peptide, CIP\u20103, binds the CD28 extracellular domain with nanomolar affinity and disrupts CD28\u2010ligand interactions. In primary human immune systems, CIP\u20103 suppresses CD28\u2010dependent T\u2010cell activation without intrinsic agonist activity and exhibits rapid pharmacologic reversibility, enabling exposure\u2010dependent control of immune signaling. In a T\u2010cell transfer model of chronic colitis, CIP\u20103 confers dose\u2010dependent therapeutic efficacy and reduces systemic inflammatory cytokines. CIP\u20103 also suppresses cytokine production across independent healthy donors and patient\u2010derived PBMCs from individuals with ulcerative colitis with efficacy comparable to a benchmark anti\u2010CD28 biologic. Together, these findings demonstrate the potential of AI\u2010designed cyclic peptides as a controllable synthetic modality for immune checkpoint modulation.<\/jats:p>","DOI":"10.1002\/advs.75892","type":"journal-article","created":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T09:46:06Z","timestamp":1780134366000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["AI\u2010Designed Cyclic Peptides Enable Controllable Modulation of the CD28 Immune Checkpoint"],"prefix":"10.1002","volume":"13","author":[{"given":"Katarzyna","family":"Kuncewicz","sequence":"first","affiliation":[{"name":"Department of Radiology Molecular Imaging Innovations Institute (MI3) Weill Cornell Medicine  New York New York USA"},{"name":"Department of Biomedical Chemistry Faculty of Chemistry University of Gdansk  Gdansk Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saurabh","family":"Upadhyay","sequence":"additional","affiliation":[{"name":"Department of Radiology Molecular Imaging Innovations Institute (MI3) Weill Cornell Medicine  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renjie","family":"Zhu","sequence":"additional","affiliation":[{"name":"Faculty of Applied Sciences Macao Polytechnic University  Macao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongliang","family":"Duan","sequence":"additional","affiliation":[{"name":"Faculty of Applied Sciences Macao Polytechnic University  Macao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moustafa T.","family":"Gabr","sequence":"additional","affiliation":[{"name":"Department of Radiology Molecular Imaging Innovations Institute (MI3) Weill Cornell Medicine  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,30]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3239"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.scib.2025.03.054"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159\u20108290.CD\u201018\u20100367"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1003466"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12885\u2010019\u20105380\u20103"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aar4060"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1080\/14740338.2025.2505542"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2025.130310"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11010\u2010025\u201005405\u2010w"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc\u20102024\u2010010530"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2026.1725349"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/cei\/uxac039"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa050524"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2020.1860476"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2399"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4305"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3236"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3229"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476\u20105381.2009.00190.x"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa063842"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010pathmechdis\u2010031521\u2010033231"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2014.09.001"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/abt\/tbaf014"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202308251"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpba.2024.116488"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.8b13178"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589\u2010023\u201001496\u2010y"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1080\/17460441.2024.2367024"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1039\/D1CB00154J"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3368"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/cimb46090627"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589\u2010025\u201001929\u2010w"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2026.103272"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010021\u201003819\u20102"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010023\u201006415\u20108"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587\u2010023\u201002115\u2010w"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.01.021"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5c00896"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbae215"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010022\u201028865\u2010w"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.94029.3"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/1074\u20107613(94)90045\u20100"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.178.1.237"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.183.6.2669"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.75892","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/advs.75892","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.75892","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T09:27:03Z","timestamp":1787909223000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.75892"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,30]]},"references-count":44,"journal-issue":{"issue":"48","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1002\/advs.75892"],"URL":"https:\/\/doi.org\/10.1002\/advs.75892","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,30]]},"assertion":[{"value":"2026-03-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-20","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e75892"}}