A CDR-based approach to generate covalent inhibitory antibody for human rhinovirus protease

[Display omitted] Covalent target modulation with small molecules has been emerging as a promising strategy for drug discovery. However, covalent inhibitory antibody remains unexplored due to the lack of efficient strategies to engineer antibody with desired bioactivity. Herein, we developed an intr...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2021-07, Vol.42, p.116219, Article 116219
Main Authors: Cheng, Yaping, Wu, Jingyuan, Han, Ying, Xu, Jingyao, Da, Yifan, Zhao, Qian, Guo, Guoying, Zhou, Yani, Chen, Yimin, Liu, Jinghong, Chen, Huayao, Jiang, Xianxing, Cai, Xiaoqing
Format: Article
Language:English
Subjects:
3C Viral Proteases - antagonists & inhibitors
3C Viral Proteases - metabolism
Antibodies - chemistry
Antibodies - pharmacology
CDR-H3
Complementarity Determining Regions - drug effects
Covalent inhibition
Cysteine Proteinase Inhibitors - chemistry
Cysteine Proteinase Inhibitors - pharmacology
Dose-Response Relationship, Drug
Humans
Inhibitory antibody
Intracellular screening
Models, Molecular
Molecular Structure
Protease 3C
Proximity-enabled bioactivity
Rhinovirus - enzymology
Structure-Activity Relationship
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Summary:[Display omitted] Covalent target modulation with small molecules has been emerging as a promising strategy for drug discovery. However, covalent inhibitory antibody remains unexplored due to the lack of efficient strategies to engineer antibody with desired bioactivity. Herein, we developed an intracellular selection method to generate covalent inhibitory antibody against human rhinovirus 14 (HRV14) 3C protease through unnatural amino acid mutagenesis along the heavy chain complementarity-determining region 3 (CDR-H3). A library of antibody mutants was thus constructed and screened in vivo through co-expression with the target protease. Using this screening strategy, six covalent antibodies with proximity-enabled bioactivity were identified, which were shown to covalently target HRV14-3C protease with high inhibitory potency and exquisite selectivity. Compared to structure-based rational design, this library-based screening method provides a simple and efficient way for the discovery and engineering of covalent antibody for enzyme inhibition.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2021.116219