Kim, J.; Chang, N.; Kim, Y.; Lee, J.; Oh, D.; Choi, J.; Kim, O.; Kim, S.; Choi, M.; Lee, J.; Lee, J.; Kim, J.; Cho, M.; Kim, M.; Lee, K.; Hwang, D.; Sa, J.K.; Park, S.; Baek, S.; Im, D. The Novel Tetra-Specific Drug C-192, Conjugated Using UniStac, Alleviates Non-Alcoholic Steatohepatitis in an MCD Diet-Induced Mouse Model. Pharmaceuticals2023, 16, 1601.
Kim, J.; Chang, N.; Kim, Y.; Lee, J.; Oh, D.; Choi, J.; Kim, O.; Kim, S.; Choi, M.; Lee, J.; Lee, J.; Kim, J.; Cho, M.; Kim, M.; Lee, K.; Hwang, D.; Sa, J.K.; Park, S.; Baek, S.; Im, D. The Novel Tetra-Specific Drug C-192, Conjugated Using UniStac, Alleviates Non-Alcoholic Steatohepatitis in an MCD Diet-Induced Mouse Model. Pharmaceuticals 2023, 16, 1601.
Kim, J.; Chang, N.; Kim, Y.; Lee, J.; Oh, D.; Choi, J.; Kim, O.; Kim, S.; Choi, M.; Lee, J.; Lee, J.; Kim, J.; Cho, M.; Kim, M.; Lee, K.; Hwang, D.; Sa, J.K.; Park, S.; Baek, S.; Im, D. The Novel Tetra-Specific Drug C-192, Conjugated Using UniStac, Alleviates Non-Alcoholic Steatohepatitis in an MCD Diet-Induced Mouse Model. Pharmaceuticals2023, 16, 1601.
Kim, J.; Chang, N.; Kim, Y.; Lee, J.; Oh, D.; Choi, J.; Kim, O.; Kim, S.; Choi, M.; Lee, J.; Lee, J.; Kim, J.; Cho, M.; Kim, M.; Lee, K.; Hwang, D.; Sa, J.K.; Park, S.; Baek, S.; Im, D. The Novel Tetra-Specific Drug C-192, Conjugated Using UniStac, Alleviates Non-Alcoholic Steatohepatitis in an MCD Diet-Induced Mouse Model. Pharmaceuticals 2023, 16, 1601.
Abstract
Non-alcoholic steatohepatitis (NASH) is a complex disease resulting from chronic liver injury associated with obesity, type 2 diabetes, and inflammation. Recently, multi-target drugs have been proposed to treat complex diseases including NASH; however, their manufacturing pro-cesses remain time- and cost-intensive and inefficient. Therefore, 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. Through such platform, 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. 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 accumula-tion, and the non-alcoholic fatty liver disease activity score. Our results collectively provide clin-ical feasibility of UniStac for developing multi-specific drugs, and C-192 as an innovative thera-peutic opportunity for severe NASH, as it exerts synergistic effects across multiple targets.
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