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Constructing Hybrid Protein Zymogens through Protective Dendritic Assembly
Author(s) -
Ng David Y. W.,
Arzt Matthias,
Wu Yuzhou,
Kuan Seah Ling,
Lamla Markus,
Weil Tanja
Publication year - 2014
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.201308533
Subject(s) - dendrimer , proteases , chemistry , papain , boronic acid , macromolecule , enzyme , biophysics , trypsin , supramolecular chemistry , cytotoxicity , intracellular , biochemistry , combinatorial chemistry , biology , organic chemistry , crystal structure , in vitro
The modulation of protein uptake and activity in response to physiological changes forms an integral part of smart protein therapeutics. We describe herein the self‐assembly of a pH‐responsive dendrimer shell onto the surface of active enzymes (trypsin, papain, DNase I) as a supramolecular protecting group to form a hybrid dendrimer–enzyme complex. The attachment is based on the interaction between boronic acid and salicyl hydroxamate, thus allowing the macromolecular assembly to respond to changes in pH between 5.0 and 7.4 in a highly reversible fashion. Catalytic activity is efficiently blocked in the presence of the dendrimer shell but is quantitatively restored upon shell degradation under acidic conditions. Unlike the native proteases, the hybrid constructs are shown to be efficiently taken up by A549 cells and colocalized in the acidic compartments. The programmed intracellular release of the proteases induced cytotoxicity, thereby uncovering a new avenue for precision biotherapeutics.