Biodegradable Amphipathic Peptide Hydrogels as Extended-Release System for Opioid Peptides

Martin, Charlotte; Dumitrascuta, Maria; Mannes, Morgane; Lantero, Aquilino; Bucher, Dominik; Walker, Katja; Wanseele, Yannick Van; Oyen, Edith; Hernot, Sophie; Eeckhaut, Ann Van; Madder, Annemieke; Hoogenboom, Richard; Spetea, Mariana; Ballet, Steven

doi:10.1021/acs.jmedchem.8b01282

Cited by 24 publications

(35 citation statements)

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“…Whereas specific binding of DALDA and [Dmt 1 ]DALDA to the MOR in the rat brain has been reported previously [ 32 ], with both ligands showing high affinity and selectivity for the MOR, in the present study the first data on binding affinity to the human MOR is reported. Binding to the human MOR was evaluated using in vitro competitive radioligand binding assays with membrane preparations from Chinese hamster ovary cells stably expressing the human MOR (CHO-hMOR cells) and the specific MOR radioligand [ 3 H]DAMGO, according to the published procedures [ 43 ]. All three peptides displayed high capability to inhibit [ 3 H]DAMGO binding to the human MOR in a concentration-dependent manner ( Figure 2 A), with binding affinities (as K i values) in the low nanomolar to subnanomolar range ( Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

“…Next, we have compared in vitro functional activities of DALDA, [Dmt 1 ]DALDA and KGOP01 at the human MOR in the guanosine-5′-O-(3-[ 35 S]thio)-triphosphate ([ 35 S]GTPγS) binding assay using membranes from CHO cells stably expressing the human MOR, performed as described [ 43 ]. All tested peptides produced a concentration-dependent increase in the [ 35 S]GTPγS binding with different levels of potencies ( Figure 2 B).…”

Section: Resultsmentioning

confidence: 99%

“…Binding assays were conducted on human MOR stably transfected into CHO cells (CHO-hMOR) according to the published procedure [ 43 ]. Cell membranes were prepared as described previously, and stored at −80 °C until use [ 43 ].…”

Section: Methodsmentioning

confidence: 99%

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Mechanistic Understanding of Peptide Analogues, DALDA, [Dmt1]DALDA, and KGOP01, Binding to the Mu Opioid Receptor

et al. 2020

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The mu opioid receptor (MOR) is the primary target for analgesia of endogenous opioid peptides, alkaloids, synthetic small molecules with diverse scaffolds, and peptidomimetics. Peptide-based opioids are viewed as potential analgesics with reduced side effects and have received constant scientific interest over the years. This study focuses on three potent peptide and peptidomimetic MOR agonists, DALDA, [Dmt1]DALDA, and KGOP01, and the prototypical peptide MOR agonist DAMGO. We present the first molecular modeling study and structure–activity relationships aided by in vitro assays and molecular docking of the opioid peptide analogues, in order to gain insight into their mode of binding to the MOR. In vitro binding and functional assays revealed the same rank order with KGOP01 > [Dmt1]DALDA > DAMGO > DALDA for both binding and MOR activation. Using molecular docking at the MOR and three-dimensional interaction pattern analysis, we have rationalized the experimental outcomes and highlighted key amino acid residues responsible for agonist binding to the MOR. The Dmt (2′,6′-dimethyl-L-Tyr) moiety of [Dmt1]DALDA and KGOP01 was found to represent the driving force for their high potency and agonist activity at the MOR. These findings contribute to a deeper understanding of MOR function and flexible peptide ligand–MOR interactions, that are of significant relevance for the future design of opioid peptide-based analgesics.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Mechanistic Understanding of Peptide Analogues, DALDA, [Dmt1]DALDA, and KGOP01, Binding to the Mu Opioid Receptor

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“…Recently, Ballet and coworkers developed new peptide‐based hydrogels as extended‐release system for opioids which formed thixotropic injectable hydrogels upon dissolution in aqueous solutions. The efficacy of the hydrogel networks as a controlled drug delivery platform was demonstrated for morphine, showing extended antinociceptive effect up to 72 h after subcutaneous administration in mice . The topical administration of opioids is an effective therapeutic method.…”

Section: Introductionmentioning

confidence: 99%

PCL microsphere/PEG‐based composite hydrogels for sustained release of methadone hydrochloride

Karamzadeh

Asl

Rahmani

2020

J of Applied Polymer Sci

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Hydrogels have increasingly received considerable attention for local opioids delivery in order to sustained wound pain relief. However, burst release of drugs is a critical problem of hydrogels. To this aim, a local drug delivery system consisting of polycaprolactone (PCL) microspheres containing methadone hydrochloride/polyethylene glycol (PEG)-based hydrogels were developed to prolong drug release with potential utilization in pain treatment. Four different drug delivery systems, including methadone hydrochloride/PEG-(N 3 ) 4 -based hydrogel, methadone hydrochloride/PEG-(N 3 ) 2 -based hydrogel, methadone hydrochloride/PCL/PEG-(N 3 ) 4 , and methadone hydrochloride/PCL/PEG-(N 3 ) 2 composite hydrogels, were fabricated to investigate drug release profiles of these systems. The results showed that drug released can be controlled by both the double-barrier matrix (hydrogel/microsphere), and the crosslinking density of hydrogels. Therefore, methadone hydrochloride/PCL/PEG-(N 3 ) 2 composite hydrogel with high crosslinking density has great potential application in sustained release systems for wound pain relief.

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“…In vitro binding assays were conducted on human opioid receptors stably transfected into CHO cells according to the published procedures 26 . Binding assays were conducted on human opioid receptors stably transfected into CHO cells (CHO-hMOR, CHOhDOR, and CHO-hKOR) according to previously published procedures 26,40 . Cell membranes were prepared as described previously 26 , and stored at − 80 °C until use.…”

Section: Pharmacology Compounds Chemicals and Reagents Corydine (1mentioning

confidence: 99%

Identification and characterization of plant-derived alkaloids, corydine and corydaline, as novel mu opioid receptor agonists

Kaserer

Steinacher

Kainhofer

et al. 2020

Sci Rep

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Pain remains a key therapeutic area with intensive efforts directed toward finding effective and safer analgesics in light of the ongoing opioid crisis. Amongst the neurotransmitter systems involved in pain perception and modulation, the mu-opioid receptor (MOR), a G protein-coupled receptor, represents one of the most important targets for achieving effective pain relief. Most clinically used opioid analgesics are agonists to the MOR, but they can also cause severe side effects. Medicinal plants represent important sources of new drug candidates, with morphine and its semisynthetic analogues as well-known examples as analgesic drugs. In this study, combining in silico (pharmacophorebased virtual screening and docking) and pharmacological (in vitro binding and functional assays, and behavioral tests) approaches, we report on the discovery of two naturally occurring plant alkaloids, corydine and corydaline, as new MOR agonists that produce antinociceptive effects in mice after subcutaneous administration via a MOR-dependent mechanism. Furthermore, corydine and corydaline were identified as G protein-biased agonists to the MOR without inducing β-arrestin2 recruitment upon receptor activation. Thus, these new scaffolds represent valuable starting points for future chemical optimization towards the development of novel opioid analgesics, which may exhibit improved therapeutic profiles. Naturally occurring opioid alkaloids, such as morphine (Fig. 1), have been used for centuries for severe and chronic pain relief 1. Over several decades, new opioids with diverse scaffolds were synthesized, pharmacologically evaluated and clinically used as the most effective class of analgesic drugs 2-5. However, all currently available opioid analgesics share a similar spectrum of undesirable side effects, including respiratory depression, constipation, sedation, nausea and analgesic tolerance 5,6. Additionally, the potential for addiction and abuse of opioids has seriously hindered their clinical application, with a huge rise in opioid misuse and overdose deaths resulting in an ongoing and rapidly emerging opioid epidemic worldwide 7,8. Currently, intensive research focuses on finding new, innovative medications and technologies to treat opioid addiction, together with the discovery of safe, effective, non-addictive drugs to manage chronic pain 9-12. Opioids produce their pharmacological effects through the activation of opioid receptors, which include three main types, mu (MOR), delta (DOR) and kappa (KOR) 13,14 , of which the MOR type is the primary target of most clinically used opioid analgesics 3,5. Opioid receptors share high homology and belong to the superfamily of seven transmembrane-spanning G protein-coupled receptors (GPCRs). Because of its therapeutic relevance, the MOR is among the few GPCRs determined in different activation states, with the first X-ray crystal structure of the receptor protein bound to β-funaltrexamine (Fig. 1), an irreversible antagonist (PDB entry 4DKL) 15 , and the 3D-structure in the active confo...

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Biodegradable Amphipathic Peptide Hydrogels as Extended-Release System for Opioid Peptides

Cited by 24 publications

References 25 publications

Mechanistic Understanding of Peptide Analogues, DALDA, [Dmt1]DALDA, and KGOP01, Binding to the Mu Opioid Receptor

Mechanistic Understanding of Peptide Analogues, DALDA, [Dmt1]DALDA, and KGOP01, Binding to the Mu Opioid Receptor

PCL microsphere/PEG‐based composite hydrogels for sustained release of methadone hydrochloride

Identification and characterization of plant-derived alkaloids, corydine and corydaline, as novel mu opioid receptor agonists

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