{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T20:11:11Z","timestamp":1790194271400,"version":"4.1.0"},"posted":{"date-parts":[[2025,10,13]]},"group-title":"Synthetic Biology","reference-count":42,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T00:00:00Z","timestamp":1760313600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000011","name":"Howard Hughes Medical Institute","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000011","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01CA114536"],"award-info":[{"award-number":["R01CA114536"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01CA240339"],"award-info":[{"award-number":["R01CA240339"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000865","name":"Bill & Melinda Gates Foundation","doi-asserted-by":"crossref","award":["INV-043758"],"award-info":[{"award-number":["INV-043758"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"crossref"}]},{"name":"IARPA Genetic Circuits program"},{"name":"DOD Breakthrough Award","award":["W81XWH-20-1-0230"],"award-info":[{"award-number":["W81XWH-20-1-0230"]}]},{"name":"Open Philanthropy Project Improving Protein Design Fund"},{"name":"Audacious Project at the Institute for Protein Design"},{"name":"Nordstrom Barrier Institute for Protein Design Directors Fund"},{"name":"Washington Research Foundation Protein Design Hub"},{"DOI":"10.13039\/100001033","name":"The Jane Coffin Childs Fund for Medical Research","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100001033","id-type":"DOI","asserted-by":"crossref"}]},{"name":"\"La Caixa\" Foundation","award":["LCF\/BQ\/AA19\/11720031"],"award-info":[{"award-number":["LCF\/BQ\/AA19\/11720031"]}]},{"DOI":"10.13039\/501100015080","name":"\"Rafael del Pino\" Foundation.","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100015080","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Cytokines regulate cell behavior by bringing together specific receptor subunits to trigger downstream signaling. Designed molecules that bring together non-natural receptor pairs could have novel signaling responses and cell specificities. We present a high-throughput de-novo design approach to create novel cytokines by generating and fusing pairs of computationally designed binders. By combining 33 designed receptor-binding domains, we generated over a thousand potential de novo designed \u201cNovokines\u201d, of which 75 activated pSTAT signaling in peripheral blood mononuclear cells. We characterized 18 of these, including new pairings of established common receptors, cross-family pairings such as TrkA-\u03b3common, and a series of pairings with interferon receptor-1 (IFNAR1), revealing that IFNAR1 can function as a versatile common receptor similar to \u03b3common or \u03b2common. We identify novokines that drive monocyte proliferation, T cell survival and CD4\n                  <jats:sup>+<\/jats:sup>\n                  T cell-specific proliferation. Our framework provides a blueprint for expanding the understanding of cytokine signaling and generating novel therapeutic proteins.\n                <\/jats:p>","DOI":"10.1101\/2025.10.12.681920","type":"posted-content","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T03:20:18Z","timestamp":1760412018000},"source":"Crossref","is-referenced-by-count":4,"title":["High-Throughput De Novo Protein Design Yields Novel Immunomodulatory Agonists"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9717-6288","authenticated-orcid":false,"given":"Mohamad","family":"Abedi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2980-303X","authenticated-orcid":false,"given":"Marc","family":"Exp\u00f2sit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6910-6255","authenticated-orcid":false,"given":"Brian","family":"Coventry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8323-7358","authenticated-orcid":false,"given":"Divij","family":"Mathew","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shruti","family":"Jain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3461-0133","authenticated-orcid":false,"given":"Aditya","family":"Krishnakumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9254-9249","authenticated-orcid":false,"given":"Inna","family":"Goreshnik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4884-5956","authenticated-orcid":false,"given":"Sophie L.","family":"Gray-Gaillard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0527-5575","authenticated-orcid":false,"given":"Margaret","family":"Lunn-Halbert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ta-Yi","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7011-8184","authenticated-orcid":false,"given":"Matthias","family":"Gl\u00f6gl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uma","family":"Mitchell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7708-6402","authenticated-orcid":false,"given":"Riya","family":"Keshri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4778-4175","authenticated-orcid":false,"given":"Jung Ho","family":"Chun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5588-4531","authenticated-orcid":false,"given":"Hannele","family":"Ruohola-Baker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0477-1956","authenticated-orcid":false,"given":"E. 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