Inhibition of the norepinephrine transporter by χ-conotoxin dendrimers

Wan, Jingjing, Brust, Andreas, Bhola, Rebecca F., Jha, Prerna, Mobli, Mehdi, Lewis, Richard J., Christie, Macdonald J. and Alewood, Paul F. (2016) Inhibition of the norepinephrine transporter by χ-conotoxin dendrimers. Journal of Peptide Science, 22 5: 280-289. doi:10.1002/psc.2857

Author Wan, Jingjing
Brust, Andreas
Bhola, Rebecca F.
Jha, Prerna
Mobli, Mehdi
Lewis, Richard J.
Christie, Macdonald J.
Alewood, Paul F.
Title Inhibition of the norepinephrine transporter by χ-conotoxin dendrimers
Journal name Journal of Peptide Science   Check publisher's open access policy
ISSN 1099-1387
Publication date 2016-05-01
Year available 2016
Sub-type Article (original research)
DOI 10.1002/psc.2857
Open Access Status Not Open Access
Volume 22
Issue 5
Start page 280
End page 289
Total pages 10
Place of publication Chichester, West Sussex, United Kingdom
Publisher John Wiley & Sons
Language eng
Formatted abstract
Peptide dendrimers are a novel class of macromolecules of emerging interest with the potential of delayed renal clearance due to their molecular size and enhanced activity due to the multivalency effect. In this work, an active analogue of the disulfide-rich χ-conotoxin χ-MrIA (χ-MrIA), a norepinephrine reuptake (norepinephrine transporter) inhibitor, was grafted onto a polylysine dendron. Dendron decoration was achieved by employing copper-catalyzed alkyne–azide cycloaddition with azido-PEG chain-modified χ-MrIA analogues, leading to homogenous 4-mer and 8-mer χ-MrIA dendrimers with molecular weights ranging from 8 to 22 kDa. These dendrimers were investigated for their impact on peptide secondary structure, in vitro functional activity, and potential anti-allodynia in vivo. NMR studies showed that the χ-MrIA tertiary structure was maintained in the χ-MrIA dendrimers. In a functional norepinephrine transporter reuptake assay, χ-MrIA dendrimers showed slightly increased potency relative to the azido-PEGylated χ-MrIA analogues with similar potency to the parent peptide. In contrast to χ-MrIA, no anti-allodynic action was observed when the χ-MrIA dendrimers were administered intrathecally in a rat model of neuropathic pain, suggesting that the larger dendrimer structures are unable to diffuse through the spinal column tissue and reach the norepinephrine transporter.
Keyword Conotoxin
Click reaction
Norepinephrine reuptake (NET) inhibitor
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 1063803
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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Institute for Molecular Bioscience - Publications
Centre for Advanced Imaging Publications
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Created: Wed, 09 Mar 2016, 22:03:33 EST by Susan Allen on behalf of Institute for Molecular Bioscience