Delivery of Antibody Mimics into Mammalian Cells via Anthrax Toxin Protective Antigen
Author(s)Liao, Xiaoli; Rabideau, Amy E.; Pentelute, Bradley L.
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Antibody mimics have significant scientific and therapeutic utility for the disruption of protein–protein interactions inside cells; however, their delivery to the cell cytosol remains a major challenge. Here we show that protective antigen (PA), a component of anthrax toxin, efficiently transports commonly used antibody mimics to the cytosol of mammalian cells when conjugated to the N-terminal domain of LF (LFN). In contrast, a cell-penetrating peptide (CPP) was not able to deliver any of these antibody mimics into the cell cytosol. The refolding and binding of a transported tandem monobody to Bcr-Abl (its protein target) in chronic myeloid leukemia cells were confirmed by co-immunoprecipitation. We also observed inhibition of Bcr-Abl kinase activity and induction of apoptosis caused by the monobody. In a separate case, we show disruption of key interactions in the MAPK signaling pathway after PA-mediated delivery of an affibody binder that targets hRaf-1. We show for the first time that PA can deliver bioactive antibody mimics to disrupt intracellular protein–protein interactions. This technology adds a useful tool to expand the applications of these modern agents to the intracellular milieu.
DepartmentMassachusetts Institute of Technology. Department of Chemistry
WILEY-VCH Verlag GmbH & Co.
Liao, Xiaoli, Amy E. Rabideau, and Bradley L. Pentelute. “Delivery of Antibody Mimics into Mammalian Cells via Anthrax Toxin Protective Antigen.” ChemBioChem, Early view, (September 22, 2014): 10 pages.
Final published version