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

Angewandte Chemie
Joong-Jae LeeHak-Sung Kim

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.

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Citations

Sep 28, 2018·Chemical Society Reviews·Yi ZhangMark D Distefano
Feb 15, 2020·Nanoscale·Yiseul RyuHak-Sung Kim
Oct 28, 2016·Biotechnology and Bioengineering·Da-Eun HwangHak-Sung Kim
Jul 19, 2016·Expert Review of Proteomics·Rebecca Christine Feiner, Kristian Mark Müller
Jan 4, 2018·Antibodies·Georg Falck, Kristian M Müller
Jul 17, 2020·Frontiers in Cell and Developmental Biology·Waseem Akram MallaAshok Kumar Tiwari
Dec 9, 2020·Chemical Society Reviews·Stephen J WalshDavid R Spring
Mar 20, 2021·Computational and Structural Biotechnology Journal·Tae Yoon KimHak-Sung Kim
Dec 6, 2016·Analytica Chimica Acta·Hyo-Deok SeoHak-Sung Kim
Apr 7, 2021·Chemical Reviews·Kiall F SuazoMark D Distefano
Sep 17, 2017·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Ayoung PyoJung-Joon Min
May 18, 2018·Journal of Medicinal Chemistry·Łukasz Joachimiak, Katarzyna M Błażewska

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