Journal
JOURNAL OF NEUROCHEMISTRY
Volume 126, Issue 2, Pages 223-233Publisher
WILEY
DOI: 10.1111/jnc.12284
Keywords
botulinum; growth factor; neuroendocrine tumor; neuropeptide; SNAP25; targeting
Categories
Funding
- MRC [U10578791]
- MRC [MC_U105178791] Funding Source: UKRI
- Medical Research Council [MC_U105178791] Funding Source: researchfish
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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.
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