Design of a Stable
Cyclic Peptide Analgesic Derived
from Sunflower Seeds that Targets the κ‑Opioid Receptor
for the Treatment of Chronic Abdominal Pain
posted on 2021-06-24, 06:34authored byEdin Muratspahić, Nataša Tomašević, Johannes Koehbach, Leopold Duerrauer, Seid Hadžić, Joel Castro, Gudrun Schober, Spyridon Sideromenos, Richard J. Clark, Stuart M. Brierley, David J. Craik, Christian W. Gruber
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.