Distribution and kinetics of the Kv1.3-blocking peptide HsTX1[R14A] in experimental rats

Abstract The peptide HsTX1[R14A] is a potent and selective blocker of the voltage-gated potassium channel Kv1.3, which is a highly promising target for the treatment of autoimmune diseases and other conditions. In order to assess the biodistribution of this peptide, it was conjugated with NOTA and r...

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Main Authors:	Ralf Bergmann, Manja Kubeil, Kristof Zarschler, Sandeep Chhabra, Rajeev B. Tajhya, Christine Beeton, Michael W. Pennington, Michael Bachmann, Raymond S. Norton, Holger Stephan
Format:	article
Language:	EN
Published:	Nature Portfolio 2017
Subjects:	Medicine R Science Q
Online Access:	https://doaj.org/article/df49b90ff84b43d9acf32897f9f258e4
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spelling	oai:doaj.org-article:df49b90ff84b43d9acf32897f9f258e42021-12-02T16:05:58ZDistribution and kinetics of the Kv1.3-blocking peptide HsTX1[R14A] in experimental rats10.1038/s41598-017-03998-x2045-2322https://doaj.org/article/df49b90ff84b43d9acf32897f9f258e42017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03998-xhttps://doaj.org/toc/2045-2322Abstract The peptide HsTX1[R14A] is a potent and selective blocker of the voltage-gated potassium channel Kv1.3, which is a highly promising target for the treatment of autoimmune diseases and other conditions. In order to assess the biodistribution of this peptide, it was conjugated with NOTA and radiolabelled with copper-64. [64Cu]Cu-NOTA-HsTX1[R14A] was synthesised in high radiochemical purity and yield. The radiotracer was evaluated in vitro and in vivo. The biodistribution and PET studies after intravenous and subcutaneous injections showed similar patterns and kinetics. The hydrophilic peptide was rapidly distributed, showed low accumulation in most of the organs and tissues, and demonstrated high molecular stability in vitro and in vivo. The most prominent accumulation occurred in the epiphyseal plates of trabecular bones. The high stability and bioavailability, low normal-tissue uptake of [64Cu]Cu-NOTA-HsTX1[R14A], and accumulation in regions of up-regulated Kv channels both in vitro and in vivo demonstrate that HsTX1[R14A] represents a valuable lead for conditions treatable by blockade of the voltage-gated potassium channel Kv1.3. The pharmacokinetics shows that both intravenous and subcutaneous applications are viable routes for the delivery of this potent peptide.Ralf BergmannManja KubeilKristof ZarschlerSandeep ChhabraRajeev B. TajhyaChristine BeetonMichael W. PenningtonMichael BachmannRaymond S. NortonHolger StephanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ralf Bergmann Manja Kubeil Kristof Zarschler Sandeep Chhabra Rajeev B. Tajhya Christine Beeton Michael W. Pennington Michael Bachmann Raymond S. Norton Holger Stephan Distribution and kinetics of the Kv1.3-blocking peptide HsTX1[R14A] in experimental rats
description	Abstract The peptide HsTX1[R14A] is a potent and selective blocker of the voltage-gated potassium channel Kv1.3, which is a highly promising target for the treatment of autoimmune diseases and other conditions. In order to assess the biodistribution of this peptide, it was conjugated with NOTA and radiolabelled with copper-64. [64Cu]Cu-NOTA-HsTX1[R14A] was synthesised in high radiochemical purity and yield. The radiotracer was evaluated in vitro and in vivo. The biodistribution and PET studies after intravenous and subcutaneous injections showed similar patterns and kinetics. The hydrophilic peptide was rapidly distributed, showed low accumulation in most of the organs and tissues, and demonstrated high molecular stability in vitro and in vivo. The most prominent accumulation occurred in the epiphyseal plates of trabecular bones. The high stability and bioavailability, low normal-tissue uptake of [64Cu]Cu-NOTA-HsTX1[R14A], and accumulation in regions of up-regulated Kv channels both in vitro and in vivo demonstrate that HsTX1[R14A] represents a valuable lead for conditions treatable by blockade of the voltage-gated potassium channel Kv1.3. The pharmacokinetics shows that both intravenous and subcutaneous applications are viable routes for the delivery of this potent peptide.
format	article
author	Ralf Bergmann Manja Kubeil Kristof Zarschler Sandeep Chhabra Rajeev B. Tajhya Christine Beeton Michael W. Pennington Michael Bachmann Raymond S. Norton Holger Stephan
author_facet	Ralf Bergmann Manja Kubeil Kristof Zarschler Sandeep Chhabra Rajeev B. Tajhya Christine Beeton Michael W. Pennington Michael Bachmann Raymond S. Norton Holger Stephan
author_sort	Ralf Bergmann
title	Distribution and kinetics of the Kv1.3-blocking peptide HsTX1[R14A] in experimental rats
title_short	Distribution and kinetics of the Kv1.3-blocking peptide HsTX1[R14A] in experimental rats
title_full	Distribution and kinetics of the Kv1.3-blocking peptide HsTX1[R14A] in experimental rats
title_fullStr	Distribution and kinetics of the Kv1.3-blocking peptide HsTX1[R14A] in experimental rats
title_full_unstemmed	Distribution and kinetics of the Kv1.3-blocking peptide HsTX1[R14A] in experimental rats
title_sort	distribution and kinetics of the kv1.3-blocking peptide hstx1[r14a] in experimental rats
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/df49b90ff84b43d9acf32897f9f258e4
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Distribution and kinetics of the Kv1.3-blocking peptide HsTX1[R14A] in experimental rats

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