title: Enzymatic prenylation and oxime ligation for the synthesis of stable and homogeneous protein-drug conjugates for targeted therapy.
abstract: 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.
authors: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon (Korea).
authors: Joong-Jae
authors: JJ
authors: Lee
authors: New Drug Research Center, LegoChem Biosciences, Inc., Daejeon (Korea).
authors: Hyo-Jung
authors: HJ
authors: Choi
authors: Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju (Korea).
authors: Misun
authors: M
authors: Yun
authors: Department of Systems Biology, Yonsei University, Seoul (Korea).
authors: YingJin
authors: Y
authors: Kang
authors: New Drug Research Center, LegoChem Biosciences, Inc., Daejeon (Korea).
authors: Ji-Eun
authors: JE
authors: Jung
authors: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon (Korea).
authors: Yiseul
authors: Y
authors: Ryu
authors: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon (Korea).
authors: Tae Yoon
authors: TY
authors: Kim
authors: Department of Systems Biology, Yonsei University, Seoul (Korea).
authors: Young-Je
authors: YJ
authors: Cha
authors: Department of Systems Biology, Yonsei University, Seoul (Korea). hscho8@yonsei.ac.kr.
authors: Hyun-Soo
authors: HS
authors: Cho
authors: Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju (Korea). jjmin@chonnam.ac.kr.
authors: Jung-Joon
authors: JJ
authors: Min
authors: New Drug Research Center, LegoChem Biosciences, Inc., Daejeon (Korea). cwchung@legochembio.com.
authors: Chul-Woong
authors: CW
authors: Chung
authors: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon (Korea). hskim76@kaist.ac.kr.
authors: Hak-Sung
authors: HS
authors: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D051231:Farnesyltranstransferase / Q000378:metabolism; D006801:Humans; D008819:Mice, Nude; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D010091:Oximes / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017368:Protein Prenylation; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D009842:Oligopeptides; D010091:Oximes; D011506:Proteins; C513576:monomethylauristatin F; D051231:Farnesyltranstransferase; D066246:ErbB Receptors
keywords: cancer; drug delivery; oxime ligation; prenylation; protein-drug conjugates