title: Constructing hybrid protein zymogens through protective dendritic assembly.
abstract: 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.
authors.affiliation: Institute of Organic Chemistry III, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm (Germany); Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz (Germany).
authors.forename: David Y W
authors.initials: DY
authors.lastname: Ng
authors.forename: Matthias
authors.initials: M
authors.lastname: Arzt
authors.forename: Yuzhou
authors.initials: Y
authors.lastname: Wu
authors.forename: Seah Ling
authors.initials: SL
authors.lastname: Kuan
authors.forename: Markus
authors.initials: M
authors.lastname: Lamla
authors.forename: Tanja
authors.initials: T
authors.lastname: Weil
mesh_terms: D050091:Dendrimers / Q000737:chemistry*; D004792:Enzyme Precursors / Q000737:chemistry*; D006801:Humans; D046911:Macromolecular Substances / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure
chemical_list: D050091:Dendrimers; D004792:Enzyme Precursors; D046911:Macromolecular Substances
keywords: dendrimers; enzymes; supramolecular chemistry