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Design of a Stable Cyclic Peptide Analgesic Derived from Sunflower Seeds that Targets the κ-Opioid Receptor for the Treatment of Chronic Abdominal Pain

[Image: see text] The rising opioid crisis has become a worldwide societal and public health burden, resulting from the abuse of prescription opioids. Targeting the κ-opioid receptor (KOR) in the periphery has emerged as a powerful approach to develop novel pain medications without central side effe...

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Autores principales: Muratspahić, Edin, Tomašević, Nataša, Koehbach, Johannes, Duerrauer, Leopold, Hadžić, Seid, Castro, Joel, Schober, Gudrun, Sideromenos, Spyridon, Clark, Richard J., Brierley, Stuart M., Craik, David J., Gruber, Christian W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2021
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273886/
https://www.ncbi.nlm.nih.gov/pubmed/34162205
http://dx.doi.org/10.1021/acs.jmedchem.1c00158
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author Muratspahić, Edin
Tomašević, Nataša
Koehbach, Johannes
Duerrauer, Leopold
Hadžić, Seid
Castro, Joel
Schober, Gudrun
Sideromenos, Spyridon
Clark, Richard J.
Brierley, Stuart M.
Craik, David J.
Gruber, Christian W.
author_facet Muratspahić, Edin
Tomašević, Nataša
Koehbach, Johannes
Duerrauer, Leopold
Hadžić, Seid
Castro, Joel
Schober, Gudrun
Sideromenos, Spyridon
Clark, Richard J.
Brierley, Stuart M.
Craik, David J.
Gruber, Christian W.
author_sort Muratspahić, Edin
collection PubMed
description [Image: see text] The rising opioid crisis has become a worldwide societal and public health burden, resulting from the abuse of prescription opioids. Targeting the κ-opioid receptor (KOR) in the periphery has emerged as a powerful approach to develop novel pain medications without central side effects. Inspired by the traditional use of sunflower (Helianthus annuus) preparations for analgesic purposes, we developed novel stabilized KOR ligands (termed as helianorphins) by incorporating different dynorphin A sequence fragments into a cyclic sunflower peptide scaffold. As a result, helianorphin-19 selectively bound to and fully activated the KOR with nanomolar potency. Importantly, helianorphin-19 exhibited strong KOR-specific peripheral analgesic activity in a mouse model of chronic visceral pain, without inducing unwanted central effects on motor coordination/sedation. Our study provides a proof of principle that cyclic peptides from plants may be used as templates to develop potent and stable peptide analgesics applicable via enteric administration by targeting the peripheral KOR for the treatment of chronic abdominal pain.
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spelling pubmed-82738862021-07-13 Design of a Stable Cyclic Peptide Analgesic Derived from Sunflower Seeds that Targets the κ-Opioid Receptor for the Treatment of Chronic Abdominal Pain Muratspahić, Edin Tomašević, Nataša Koehbach, Johannes Duerrauer, Leopold Hadžić, Seid Castro, Joel Schober, Gudrun Sideromenos, Spyridon Clark, Richard J. Brierley, Stuart M. Craik, David J. Gruber, Christian W. J Med Chem [Image: see text] The rising opioid crisis has become a worldwide societal and public health burden, resulting from the abuse of prescription opioids. Targeting the κ-opioid receptor (KOR) in the periphery has emerged as a powerful approach to develop novel pain medications without central side effects. Inspired by the traditional use of sunflower (Helianthus annuus) preparations for analgesic purposes, we developed novel stabilized KOR ligands (termed as helianorphins) by incorporating different dynorphin A sequence fragments into a cyclic sunflower peptide scaffold. As a result, helianorphin-19 selectively bound to and fully activated the KOR with nanomolar potency. Importantly, helianorphin-19 exhibited strong KOR-specific peripheral analgesic activity in a mouse model of chronic visceral pain, without inducing unwanted central effects on motor coordination/sedation. Our study provides a proof of principle that cyclic peptides from plants may be used as templates to develop potent and stable peptide analgesics applicable via enteric administration by targeting the peripheral KOR for the treatment of chronic abdominal pain. American Chemical Society 2021-06-24 2021-07-08 /pmc/articles/PMC8273886/ /pubmed/34162205 http://dx.doi.org/10.1021/acs.jmedchem.1c00158 Text en © 2021 The Authors. Published by American Chemical Society Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Muratspahić, Edin
Tomašević, Nataša
Koehbach, Johannes
Duerrauer, Leopold
Hadžić, Seid
Castro, Joel
Schober, Gudrun
Sideromenos, Spyridon
Clark, Richard J.
Brierley, Stuart M.
Craik, David J.
Gruber, Christian W.
Design of a Stable Cyclic Peptide Analgesic Derived from Sunflower Seeds that Targets the κ-Opioid Receptor for the Treatment of Chronic Abdominal Pain
title Design of a Stable Cyclic Peptide Analgesic Derived from Sunflower Seeds that Targets the κ-Opioid Receptor for the Treatment of Chronic Abdominal Pain
title_full Design of a Stable Cyclic Peptide Analgesic Derived from Sunflower Seeds that Targets the κ-Opioid Receptor for the Treatment of Chronic Abdominal Pain
title_fullStr Design of a Stable Cyclic Peptide Analgesic Derived from Sunflower Seeds that Targets the κ-Opioid Receptor for the Treatment of Chronic Abdominal Pain
title_full_unstemmed Design of a Stable Cyclic Peptide Analgesic Derived from Sunflower Seeds that Targets the κ-Opioid Receptor for the Treatment of Chronic Abdominal Pain
title_short Design of a Stable Cyclic Peptide Analgesic Derived from Sunflower Seeds that Targets the κ-Opioid Receptor for the Treatment of Chronic Abdominal Pain
title_sort design of a stable cyclic peptide analgesic derived from sunflower seeds that targets the κ-opioid receptor for the treatment of chronic abdominal pain
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273886/
https://www.ncbi.nlm.nih.gov/pubmed/34162205
http://dx.doi.org/10.1021/acs.jmedchem.1c00158
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