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- Title
Enzymatic Prenylation and Oxime Ligation for the Synthesis of Stable and Homogeneous Protein-Drug Conjugates for Targeted Therapy.
- Authors
Lee, Joong‐jae; Choi, Hyo‐Jung; Yun, Misun; Kang, YingJin; Jung, Ji‐Eun; Ryu, Yiseul; Kim, Tae Yoon; Cha, Young‐je; Cho, Hyun‐Soo; Min, Jung‐Joon; Chung, Chul‐Woong; Kim, Hak‐Sung
- 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.
- Subjects
ISOPRENYLATION; OXIMES; ANTIBODY-drug conjugates; HOMOGENEOUS catalysis; PROTEIN binding
- Publication
Angewandte Chemie International Edition, 2015, Vol 54, Issue 41, p12020
- ISSN
1433-7851
- Publication type
Article
- DOI
10.1002/anie.201505964