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Enzymatic Prenylation and Oxime Ligation for the Synthesis of Stable and Homogeneous Protein–Drug Conjugates for Targeted Therapy
Author(s) -
Lee Joongjae,
Choi HyoJung,
Yun Misun,
Kang YingJin,
Jung JiEun,
Ryu Yiseul,
Kim Tae Yoon,
Cha Youngje,
Cho HyunSoo,
Min JungJoon,
Chung ChulWoong,
Kim HakSung
Publication year - 2015
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201505964
Subject(s) - conjugate , farnesyltransferase , drug , chemistry , nanocarriers , oxime , combinatorial chemistry , in vivo , prenylation , pharmacology , enzyme , biochemistry , medicine , biology , mathematical analysis , mathematics , microbiology and biotechnology
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.