Duplication of clostridial binding domains for enhanced macromolecular delivery into neurons.
Botulinum
Double
Duplicated
Multivalent
Neuronal delivery
Tetanus
Journal
Toxicon: X
ISSN: 2590-1710
Titre abrégé: Toxicon X
Pays: England
ID NLM: 101741983
Informations de publication
Date de publication:
Mar 2020
Mar 2020
Historique:
received:
16
08
2019
revised:
25
11
2019
accepted:
19
12
2019
entrez:
7
3
2020
pubmed:
7
3
2020
medline:
7
3
2020
Statut:
ppublish
Résumé
Neurological diseases constitute a quarter of global disease burden and are expected to rise worldwide with the ageing of human populations. There is an increasing need to develop new molecular systems which can deliver drugs specifically into neurons, non-dividing cells meant to last a human lifetime. Neuronal drug delivery must rely on agents which can recognise neurons with high specificity and affinity. Here we used a recently introduced 'stapling' system to prepare macromolecules carrying duplicated binding domains from the clostridial family of neurotoxins. We engineered individual parts of clostridial neurotoxins separately and combined them using a strong alpha-helical bundle. We show that combining two identical binding domains of tetanus and botulinum type D neurotoxins, in a sterically defined way by protein stapling, allows enhanced intracellular delivery of molecules into neurons. We also engineered a botulinum neurotoxin type C variant with a duplicated binding domain which increased enzymatic delivery compared to the native type C toxin. We conclude that duplication of the binding parts of tetanus or botulinum neurotoxins will allow production of high avidity agents which could deliver imaging reagents and large therapeutic enzymes into neurons with superior efficiency.
Identifiants
pubmed: 32140681
doi: 10.1016/j.toxcx.2019.100019
pii: S2590-1710(19)30016-5
pii: 100019
pmc: PMC7043326
doi:
Types de publication
Journal Article
Langues
eng
Pagination
100019Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Informations de copyright
© 2020 The Authors.
Déclaration de conflit d'intérêts
The authors have no competing interests to declare.
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