The Novel Tetra-Specific Drug C-192, Conjugated Using UniStac, Alleviates Non-Alcoholic Steatohepatitis in an MCD Diet-Induced Mouse Model
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Published:2023-11-13
Issue:11
Volume:16
Page:1601
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ISSN:1424-8247
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Container-title:Pharmaceuticals
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language:en
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Short-container-title:Pharmaceuticals
Author:
Kim Jihye1, Chang Nakho1, Kim Yunki1, Lee Jaehyun1, Oh Daeseok1, Choi Jaeyoung1, Kim Onyou1, Kim Sujin1, Choi Myongho1, Lee Junyeob1, Lee Junghwa1, Kim Jungyul1, Cho Minji1, Kim Minsu1, Lee Kwanghwan1, Hwang Dukhyun1, Sa Jason K.2, Park Sungjin1, Baek Seungjae3ORCID, Im Daeseong1ORCID
Affiliation:
1. Onegene Biotechnology, Inc., 205 Ace Gwanggyo Tower 2, 91 Changnyong-daero 256 beon-gil, Yeongtong-gu, Suwon-si 16229, Republic of Korea 2. Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Republic of Korea 3. Department of Biomedical Engineering, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea
Abstract
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.
Funder
This research was supported by Korea Drug Development Fund funded by Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare
Subject
Drug Discovery,Pharmaceutical Science,Molecular Medicine
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