Duplication of clostridial binding domains for enhanced macromolecular delivery into neurons.

Toxicon: X
Charlotte LeeseBazbek Davletov

Abstract

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 ...Continue Reading

References

Mar 25, 1993·Nature·T SöllnerJ E Rothman
Jun 18, 2004·Journal of Neurology, Neurosurgery, and Psychiatry·J Jankovic
Oct 13, 2007·Pharmaceutical Research·Jamie M BergenSuzie H Pun
Mar 18, 2010·Annual Review of Biochemistry·Mauricio Montal
Oct 6, 2010·Proceedings of the National Academy of Sciences of the United States of America·Frédéric DariosBazbek Davletov
Nov 10, 2011·Toxins·Janne M ToivonenRosario Osta
Jun 5, 2012·Cell Calcium·Bazbek DavletovYuri Ushkaryov
Sep 4, 2012·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Jiafu WangJ Oliver Dolly
Sep 10, 2013·Bioconjugate Chemistry·Enrico FerrariBazbek Davletov
Jun 13, 2014·The EMBO Journal·Marco TerenzioGiampietro Schiavo
Jul 1, 2014·Nature Reviews. Microbiology·Ornella RossettoCesare Montecucco
May 18, 2016·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·René RoyHans-Joachim Gabius
Oct 11, 2016·Trends in Molecular Medicine·Saak V OvsepianJ Oliver Dolly
Feb 22, 2017·Scientific Reports·Edwin J Vazquez-CintronKonstantin Ichtchenko
Oct 17, 2017·Toxicon : Official Journal of the International Society on Toxinology·Sunaina SuranaGiampietro Schiavo
Jan 27, 2018·Toxicology in Vitro : an International Journal Published in Association with BIBRA·B GrayM Beard
May 24, 2018·Cell Death & Disease·Katherine L GibbsGiampietro Schiavo
Aug 28, 2018·Expert Opinion on Investigational Drugs·Christoph Stein
Aug 28, 2018·Pharmacology & Therapeutics·Saak V OvsepianJames O Dolly
Apr 3, 2019·Lancet·Lam Minh Yen, C Louise Thwaites

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Methods Mentioned

BETA
gel-filtration
gel filtration
electrophoresis
protein assay
X-Ray
Fluorescence

Software Mentioned

MicroManager
Image Studio
FIJI
Quantity One
Motion Analysis
GraphPad Prism
Kinetic Imaging )

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