{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T14:25:15Z","timestamp":1785767115541,"version":"3.56.0"},"reference-count":69,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T00:00:00Z","timestamp":1699833600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Ministry of Science and ICT, the Ministry of Trade, Industry, and Energy, and the Ministry of Health and Welfare","award":["HN21C0561"],"award-info":[{"award-number":["HN21C0561"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Non-alcoholic steatohepatitis (NASH) is a complex disease resulting from chronic liver injury associated with obesity, type 2 diabetes, and inflammation. Recently, the importance of developing multi-target drugs as a strategy to address complex diseases such as NASH has been growing; however, their manufacturing processes remain time- and cost-intensive and inefficient. To overcome these limitations, we developed UniStac, a novel enzyme-mediated conjugation platform for multi-specific drug development. UniStac demonstrated high conjugation yields, optimal thermal stabilities, and robust biological activities. We designed a tetra-specific compound, C-192, targeting glucagon-like peptide 1 (GLP-1), glucagon (GCG), fibroblast growth factor 21 (FGF21), and interleukin-1 receptor antagonist (IL-1RA) simultaneously for the treatment of NASH using UniStac. The biological activity and treatment efficacy of C-192 were confirmed both in vitro and in vivo using a methionine-choline-deficient (MCD) diet-induced mouse model. C-192 exhibited profound therapeutic efficacies compared to conventional drugs, including liraglutide and dulaglutide. C-192 significantly improved alanine transaminase levels, triglyceride accumulation, and the non-alcoholic fatty liver disease activity score. In this study, we demonstrated the feasibility of UniStac in creating multi-specific drugs and confirmed the therapeutic potential of C-192, a drug that integrates multiple mechanisms into a single molecule for the treatment of NASH.<\/jats:p>","DOI":"10.3390\/ph16111601","type":"journal-article","created":{"date-parts":[[2023,11,14]],"date-time":"2023-11-14T02:20:37Z","timestamp":1699928437000},"page":"1601","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Novel Tetra-Specific Drug C-192, Conjugated Using UniStac, Alleviates Non-Alcoholic Steatohepatitis in an MCD Diet-Induced Mouse Model"],"prefix":"10.3390","volume":"16","author":[{"given":"Jihye","family":"Kim","sequence":"first","affiliation":[{"name":"Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nakho","family":"Chang","sequence":"additional","affiliation":[{"name":"Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunki","family":"Kim","sequence":"additional","affiliation":[{"name":"Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaehyun","family":"Lee","sequence":"additional","affiliation":[{"name":"Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daeseok","family":"Oh","sequence":"additional","affiliation":[{"name":"Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaeyoung","family":"Choi","sequence":"additional","affiliation":[{"name":"Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Onyou","family":"Kim","sequence":"additional","affiliation":[{"name":"Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sujin","family":"Kim","sequence":"additional","affiliation":[{"name":"Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myongho","family":"Choi","sequence":"additional","affiliation":[{"name":"Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyeob","family":"Lee","sequence":"additional","affiliation":[{"name":"Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junghwa","family":"Lee","sequence":"additional","affiliation":[{"name":"Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jungyul","family":"Kim","sequence":"additional","affiliation":[{"name":"Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minji","family":"Cho","sequence":"additional","affiliation":[{"name":"Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minsu","family":"Kim","sequence":"additional","affiliation":[{"name":"Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwanghwan","family":"Lee","sequence":"additional","affiliation":[{"name":"Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dukhyun","family":"Hwang","sequence":"additional","affiliation":[{"name":"Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason K.","family":"Sa","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sungjin","family":"Park","sequence":"additional","affiliation":[{"name":"Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of 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