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  3. Enzymatic prenylation and oxime ligation for the synthesis of stable and homogeneous protein-drug conjugates for targeted therapy

Enzymatic prenylation and oxime ligation for the synthesis of stable and homogeneous protein-drug conjugates for targeted therapy

  • Angew Chem Int Ed Engl. 2015 Oct 5;54(41):12020-4. doi: 10.1002/anie.201505964.
Joong-Jae Lee 1,  Hyo-Jung Choi 2,  Misun Yun 3,  YingJin Kang 4,  Ji-Eun Jung 2,  Yiseul Ryu 1,  Tae Yoon Kim 1,  Young-Je Cha 4,  Hyun-Soo Cho 5,  Jung-Joon Min 6,  Chul-Woong Chung 7,  Hak-Sung Kim 8
Affiliations

Affiliations

  • 1 Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon (Korea).
  • 2 New Drug Research Center, LegoChem Biosciences, Inc., Daejeon (Korea).
  • 3 Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju (Korea).
  • 4 Department of Systems Biology, Yonsei University, Seoul (Korea).
  • 5 Department of Systems Biology, Yonsei University, Seoul (Korea). hscho8@yonsei.ac.kr.
  • 6 Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju (Korea). jjmin@chonnam.ac.kr.
  • 7 New Drug Research Center, LegoChem Biosciences, Inc., Daejeon (Korea). cwchung@legochembio.com.
  • 8 Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon (Korea). hskim76@kaist.ac.kr.
PMID: 26315561 DOI: 10.1002/anie.201505964
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.

Keywords

cancer; drug delivery; oxime ligation; prenylation; protein-drug conjugates.

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