Stapling of the botulinum type A protease to growth factors and neuropeptides allows selective targeting of neuroendocrine cells

Arsenault, Jason and Ferrari, Enrico and Niranjan, Dhevahi and Cuijpers, Sabine A. G. and Gu, Chunjing and Vallis, Yvonne and O'Brien, John and Davletov, Bazbek (2013) Stapling of the botulinum type A protease to growth factors and neuropeptides allows selective targeting of neuroendocrine cells. Journal of Neurochemistry, 126 (2). pp. 223-233. ISSN 0022-3042

Full content URL: http://dx.doi.org/10.1111/jnc.12284

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Abstract

Precise cellular targeting of macromolecular cargos has important biotechnological and medical implications. Using a recently established ‘protein stapling’ method, we linked the proteolytic domain of botulinum neurotoxin type A (BoNT/A) to a selection of ligands to target neuroendocrine tumor cells. The botulinum proteolytic domain was chosen because of its well-known potency to block the release of neurotransmitters and hormones. Among nine tested stapled ligands, the epidermal growth factor was able to deliver the botulinum enzyme into pheochromocytoma PC12 and insulinoma Min6 cells; ciliary neurotrophic factor was effective on neuroblastoma SH-SY5Y and Neuro2A cells, whereas corticotropin-releasing hormone was active on pituitary AtT-20 cells and the two neuroblastoma cell lines. In neuronal cultures, the epidermal growth factor- and ciliary neurotrophic factor-directed botulinum enzyme targeted distinct subsets of neurons whereas the whole native neurotoxin targeted the cortical neurons indiscriminately. At nanomolar concentrations, the retargeted botulinum molecules were able to inhibit stimulated release of hormones from tested cell lines suggesting their application for treatments of neuroendocrine disorders.

Keywords:botulinum, growth factor, neuroendocrine tumor, neuropeptide, SNAP25, targeting
Subjects:B Subjects allied to Medicine > B140 Neuroscience
C Biological Sciences > C560 Biotechnology
C Biological Sciences > C700 Molecular Biology, Biophysics and Biochemistry
Divisions:College of Science > School of Life Sciences
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ID Code:11318
Deposited On:23 Jul 2013 14:49

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