title: A Supramolecular Approach toward Bioinspired PAMAM-Dendronized Fusion Toxins.
abstract: Nature has provided a highly optimized toolbox in bacterial endotoxins with precise functions dictated by their clear structural division. Inspired by this streamlined design, a supramolecular approach capitalizing on the strong biomolecular (streptavidin (SA))-biotin interactions is reported herein to prepare two multipartite fusion constructs, which involves the generation 2.0 (D2) or generation 3.0 (D3) polyamidoamine-dendronized transporter proteins (dendronized streptavidin (D3SA) and dendronized human serum albumin (D2HSA)) non-covalently fused to the C3bot1 enzyme from Clostridium botulinum, a potent and specific Rho-inhibitor. The fusion constructs, D3SA-C3 and D2HSA-C3, represent the first examples of dendronized protein transporters that are fused to the C3 enzyme, and it is successfully demonstrated that the C3 Rho-inhibitor is delivered into the cytosol of mammalian cells as determined from the characteristic C3-mediated changes in cell morphology and confocal microscopy. The design circumvents the low uptake of the C3 enzyme by eukaryotic cells and holds great promise for reprogramming the properties of toxin enzymes using a supramolecular approach to broaden their therapeutic applications.
authors.affiliation: Institute of Organic Chemistry III - Macromolecular Chemistry & Biomaterials, University of Ulm, Albert-Einstein-Allee 11, 89081, Ulm, Germany.
authors.forename: Seah Ling
authors.initials: SL
authors.lastname: Kuan
authors.affiliation: Institute of Pharmacology and Toxicology, University of Ulm Medical Center, Albert-Einstein-Allee 11, 89081, Ulm, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Förtsch
authors.affiliation: Institute of Organic Chemistry III - Macromolecular Chemistry & Biomaterials, University of Ulm, Albert-Einstein-Allee 11, 89081, Ulm, Germany.
authors.forename: David Yuen Wah
authors.initials: DY
authors.lastname: Ng
authors.affiliation: Institute of Pharmacology and Toxicology, University of Ulm Medical Center, Albert-Einstein-Allee 11, 89081, Ulm, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Fischer
authors.affiliation: Institute of Organic Chemistry III - Macromolecular Chemistry & Biomaterials, University of Ulm, Albert-Einstein-Allee 11, 89081, Ulm, Germany.
authors.forename: Yu
authors.initials: Y
authors.lastname: Tokura
authors.affiliation: Institute of Organic Chemistry III - Macromolecular Chemistry & Biomaterials, University of Ulm, Albert-Einstein-Allee 11, 89081, Ulm, Germany.
authors.forename: Weina
authors.initials: W
authors.lastname: Liu
authors.affiliation: Institute of Organic Chemistry III - Macromolecular Chemistry & Biomaterials, University of Ulm, Albert-Einstein-Allee 11, 89081, Ulm, Germany.
authors.forename: Yuzhou
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Max Planck Institute for Polymer Research, Ackermannweg 10, 55128, Mainz, Germany.
authors.forename: Kaloian
authors.initials: K
authors.lastname: Koynov
authors.affiliation: Institute of Pharmacology and Toxicology, University of Ulm Medical Center, Albert-Einstein-Allee 11, 89081, Ulm, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Barth
authors.affiliation: Institute of Organic Chemistry III - Macromolecular Chemistry & Biomaterials, University of Ulm, Albert-Einstein-Allee 11, 89081, Ulm, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Weil
mesh_terms: D036002:ADP Ribose Transferases / Q000737:chemistry / Q000494:pharmacology*; D001710:Biotin / Q000737:chemistry; D001905:Botulinum Toxins / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003014:Clostridium botulinum / Q000201:enzymology; D003600:Cytosol / Q000187:drug effects; D050091:Dendrimers / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008264:Macrophages / Q000187:drug effects; D012709:Serum Albumin / Q000737:chemistry; D019809:Streptavidin / Q000737:chemistry; D014118:Toxins, Biological / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D050091:Dendrimers; C104700:PAMAM Starburst; D012709:Serum Albumin; D014118:Toxins, Biological; D001710:Biotin; D019809:Streptavidin; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D001905:Botulinum Toxins
keywords: C3 enzymes; bioinspired fusion toxins; dendronized protein transporters; polyamidoamine dendrimer