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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Nature Portfolio
2017
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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) |
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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 |
work_keys_str_mv |
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1718385179554217984 |