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

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.

journal_name

J Neurochem

authors

Arsenault J,Ferrari E,Niranjan D,Cuijpers SA,Gu C,Vallis Y,O'Brien J,Davletov B

doi

10.1111/jnc.12284

subject

Has Abstract

pub_date

2013-07-01 00:00:00

pages

223-33

issue

2

eissn

0022-3042

issn

1471-4159

journal_volume

126

pub_type

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