1. Inhibition of the norepinephrine transporter by χ-conotoxin dendrimers.
- Author
-
Wan J, Brust A, Bhola RF, Jha P, Mobli M, Lewis RJ, Christie MJ, and Alewood PF
- Subjects
- Animals, COS Cells, Chemistry Techniques, Synthetic methods, Click Chemistry, Conotoxins chemical synthesis, Conotoxins chemistry, Conotoxins pharmacology, Cycloaddition Reaction, Dendrimers administration & dosage, Dendrimers chemistry, Dendrimers pharmacology, Disease Models, Animal, Disulfides chemistry, Drug Design, Models, Molecular, Protein Structure, Secondary, Protein Structure, Tertiary, Rats, Structure-Activity Relationship, Conotoxins administration & dosage, Dendrimers chemical synthesis, Hyperalgesia drug therapy, Norepinephrine Plasma Membrane Transport Proteins antagonists & inhibitors
- 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. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd., (Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.)
- Published
- 2016
- Full Text
- View/download PDF