Enzymatic Prenylation and Oxime Ligation for the Synthesis of Stable and Homogeneous Protein–Drug Conjugates for Targeted Therapy
Dr. Joong-jae Lee
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon (Korea)
These authors contributed equally to this work.
Search for more papers by this authorHyo-Jung Choi
New Drug Research Center, LegoChem Biosciences, Inc., Daejeon (Korea)
These authors contributed equally to this work.
Search for more papers by this authorMisun Yun
Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju (Korea)
These authors contributed equally to this work.
Search for more papers by this authorYingJin Kang
Department of Systems Biology, Yonsei University, Seoul (Korea)
These authors contributed equally to this work.
Search for more papers by this authorJi-Eun Jung
New Drug Research Center, LegoChem Biosciences, Inc., Daejeon (Korea)
Search for more papers by this authorDr. Yiseul Ryu
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon (Korea)
Search for more papers by this authorTae Yoon Kim
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon (Korea)
Search for more papers by this authorYoung-je Cha
Department of Systems Biology, Yonsei University, Seoul (Korea)
Search for more papers by this authorCorresponding Author
Prof. Hyun-Soo Cho
Department of Systems Biology, Yonsei University, Seoul (Korea)
Hyun-Soo Cho, Department of Systems Biology, Yonsei University, Seoul (Korea)
Jung-Joon Min, Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju (Korea)
Chul-Woong Chung, New Drug Research Center, LegoChem Biosciences, Inc., Daejeon (Korea)
Hak-Sung Kim, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon (Korea)
Search for more papers by this authorCorresponding Author
Prof. Jung-Joon Min
Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju (Korea)
Hyun-Soo Cho, Department of Systems Biology, Yonsei University, Seoul (Korea)
Jung-Joon Min, Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju (Korea)
Chul-Woong Chung, New Drug Research Center, LegoChem Biosciences, Inc., Daejeon (Korea)
Hak-Sung Kim, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon (Korea)
Search for more papers by this authorCorresponding Author
Dr. Chul-Woong Chung
New Drug Research Center, LegoChem Biosciences, Inc., Daejeon (Korea)
Hyun-Soo Cho, Department of Systems Biology, Yonsei University, Seoul (Korea)
Jung-Joon Min, Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju (Korea)
Chul-Woong Chung, New Drug Research Center, LegoChem Biosciences, Inc., Daejeon (Korea)
Hak-Sung Kim, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon (Korea)
Search for more papers by this authorCorresponding Author
Prof. Hak-Sung Kim
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon (Korea)
Hyun-Soo Cho, Department of Systems Biology, Yonsei University, Seoul (Korea)
Jung-Joon Min, Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju (Korea)
Chul-Woong Chung, New Drug Research Center, LegoChem Biosciences, Inc., Daejeon (Korea)
Hak-Sung Kim, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon (Korea)
Search for more papers by this authorDr. Joong-jae Lee
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon (Korea)
These authors contributed equally to this work.
Search for more papers by this authorHyo-Jung Choi
New Drug Research Center, LegoChem Biosciences, Inc., Daejeon (Korea)
These authors contributed equally to this work.
Search for more papers by this authorMisun Yun
Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju (Korea)
These authors contributed equally to this work.
Search for more papers by this authorYingJin Kang
Department of Systems Biology, Yonsei University, Seoul (Korea)
These authors contributed equally to this work.
Search for more papers by this authorJi-Eun Jung
New Drug Research Center, LegoChem Biosciences, Inc., Daejeon (Korea)
Search for more papers by this authorDr. Yiseul Ryu
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon (Korea)
Search for more papers by this authorTae Yoon Kim
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon (Korea)
Search for more papers by this authorYoung-je Cha
Department of Systems Biology, Yonsei University, Seoul (Korea)
Search for more papers by this authorCorresponding Author
Prof. Hyun-Soo Cho
Department of Systems Biology, Yonsei University, Seoul (Korea)
Hyun-Soo Cho, Department of Systems Biology, Yonsei University, Seoul (Korea)
Jung-Joon Min, Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju (Korea)
Chul-Woong Chung, New Drug Research Center, LegoChem Biosciences, Inc., Daejeon (Korea)
Hak-Sung Kim, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon (Korea)
Search for more papers by this authorCorresponding Author
Prof. Jung-Joon Min
Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju (Korea)
Hyun-Soo Cho, Department of Systems Biology, Yonsei University, Seoul (Korea)
Jung-Joon Min, Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju (Korea)
Chul-Woong Chung, New Drug Research Center, LegoChem Biosciences, Inc., Daejeon (Korea)
Hak-Sung Kim, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon (Korea)
Search for more papers by this authorCorresponding Author
Dr. Chul-Woong Chung
New Drug Research Center, LegoChem Biosciences, Inc., Daejeon (Korea)
Hyun-Soo Cho, Department of Systems Biology, Yonsei University, Seoul (Korea)
Jung-Joon Min, Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju (Korea)
Chul-Woong Chung, New Drug Research Center, LegoChem Biosciences, Inc., Daejeon (Korea)
Hak-Sung Kim, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon (Korea)
Search for more papers by this authorCorresponding Author
Prof. Hak-Sung Kim
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon (Korea)
Hyun-Soo Cho, Department of Systems Biology, Yonsei University, Seoul (Korea)
Jung-Joon Min, Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju (Korea)
Chul-Woong Chung, New Drug Research Center, LegoChem Biosciences, Inc., Daejeon (Korea)
Hak-Sung Kim, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon (Korea)
Search for more papers by this authorAbstract
Targeted therapy based on protein–drug conjugates has attracted significant attention owing to its high efficacy and low side effects. However, efficient and stable drug conjugation to a protein binder remains a challenge. Herein, a chemoenzymatic method to generate highly stable and homogenous drug conjugates with high efficiency is presented. The approach comprises the insertion of the CaaX sequence at the C-terminal end of the protein binder, prenylation using farnesyltransferase, and drug conjugation through an oxime ligation reaction. MMAF and an EGFR-specific repebody are used as the antitumor agent and protein binder, respectively. The method enables the precisely controlled synthesis of repebody–drug conjugates with high yield and homogeneity. The utility of this approach is illustrated by the notable stability of the repebody–drug conjugates in human plasma, negligible off-target effects, and a remarkable antitumor activity in vivo. The present method can be widely used for generating highly homogeneous and stable PDCs for targeted therapy.
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