Abstract
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.
Highlights
G protein-coupled receptors (GPCRs) continue to be among the most important drug targets, with small-molecule ligands of these receptors currently dominating the pharmaceutical market.[1]
The sunflower trypsin inhibitor-1 (SFTI-1) is a 14residue cyclic peptide derived from the seeds of sunflowers (Figure 1A,B) that is stabilized by one disulfide bond, exhibiting a less-complex structure while retaining high stability.[11]
The analgesic activity of a methanolic extract of sunflower seeds was reported[28] and prompted us to investigate whether SFTI-1, one of the main peptides in the extract of sunflower seeds (Figure 1A,B), might be a novel ligand of the KOR
Summary
G protein-coupled receptors (GPCRs) continue to be among the most important drug targets, with small-molecule ligands of these receptors currently dominating the pharmaceutical market.[1]. Regardless of the epitope sequences, the lysine residue (K) in the binding loop was replaced with alanine (A) to eliminate trypsin inhibitory activity of SFTI-1.37 These peptides were examined in KOR binding experiments via two-point radioligand displacement studies A detailed pharmacological analysis of helianorphin-12 revealed that the peptide binds to and fully activates the KOR in a concentration-dependent manner with a Ki of 2.4 μM and an EC50 of 1.4 μM, respectively (Table 1, Figure S1B, Supporting Information). Mice jumped at similar intensity upon administration of helianorphin-19 and U50,488 when compared to those with a vehicle (Figure 6D) Taken together, these findings highlight the potential of the nature-derived cyclic peptide scaffolds to design and develop novel peripheral KOR analgesics
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