Backbone Cyclization Turns a Venom Peptide into a Stable and Equipotent Ligand at Both Muscle and Neuronal Nicotinic Receptors

Giribaldi, Julien; Haufe, Yves; Evans, Edward R. J.; Amar, Muriel; Durner, Anna; Schmidt, Casey A.; Faucherre, Adèle; Maati, Hamid Moha Ou; Enjalbal, Christine; Molgó, Jordi; Servent, Denis; Wilson, David T.; Daly, Norelle L.; Nicke, Annette; Dutertre, Sébastien

doi:10.1021/acs.jmedchem.0c00957

Cited by 13 publications

(13 citation statements)

References 44 publications

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“…The only α9-selective antagonists identified prior to this study have been conotoxins such as RgIA4 26 and peptide toxins, which are difficult to synthesize and purify and generally impractical as therapeutic agents, due to stability and bioavailability issues. 36 Likewise, previously there have been no reports of α9α10selective agonists, and several common nAChR agonists such as nicotine, cytisine, and epibatidine are, in fact, antagonists of these receptors. 6 Our results, therefore, represent several new opportunities for investigating the function of α9α10 nAChR and potential new directions for the development of therapeutics.…”

Section: ■ Introductionmentioning

confidence: 99%

Selective Agonists and Antagonists of α9 Versus α7 Nicotinic Acetylcholine Receptors

Papke

Andleeb

Stokes

et al. 2022

ACS Chem. Neurosci.

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Nicotinic acetylcholine receptors containing α9 subunits are essential for the auditory function and have been implicated, along with α7containing nicotinic receptors, as potential targets for the treatment of inflammatory and neuropathic pain. The study of α9-containing receptors has been hampered by the lack of selective agonists. The only α9-selective antagonists previously identified are peptide conotoxins. Curiously, the activity of α7 and α9 receptors as modulators of inflammatory pain appears to not rely strictly on ion channel activation, which led to the identification of α7 "silent agonists" and phosphocholine as an "unconventional agonist" for α9 containing receptors. The parallel testing of the α7 silent agonist p-CF 3 −diEPP and phosphocholine led to the discovery that p-CF 3 −diEPP was an α9 agonist. In this report, we compared the activity of α7 and α9 with a family of structurally related compounds, most of which were previously shown to be α7 partial or silent agonists. We identify several potent α9-selective agonists as well as numerous potent and selective α9 antagonists and describe the structural basis for these activities. Several of these compounds have previously been shown to be effective in animal models of inflammatory pain, an activity that was assumed to be due to α7 silent agonism but may, in fact, be due to α9 activity. The α9-selective conotoxin antagonists have also been shown to reduce pain in similar models. Our identification of these new α9 agonists and antagonists may prove to be invaluable for defining an optimal approach for treating pain, allowing for reduced use of opioid drugs.

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Section: ■ Introductionmentioning

confidence: 99%

Selective Agonists and Antagonists of α9 Versus α7 Nicotinic Acetylcholine Receptors

Papke

Andleeb

Stokes

et al. 2022

ACS Chem. Neurosci.

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“…Strategies including dicarba, saturated dicarba, alkyne, thioether, ether, diselenide (Sec), penicillamine-cysteine (Pen-Cys) hybrid, and triazole bridge replacement have been extensively applied in CTx modifications (Figure C). − However, such strategies lack broad applicability owing to incompatibility of the mimetic moiety with bioactivity and toxicity. Head-to-tail backbone cyclization is another investigated strategy to improve peptide stability through prevention of degradation as it stabilized the structure and reduced proteolysis susceptibility. − Nevertheless, the application of this method to RgIA resulted in obvious potency drop on α9α10 nAChR binding affinity. − …”

Section: Introductionmentioning

confidence: 99%

Discovery of Methylene Thioacetal-Incorporated α-RgIA Analogues as Potent and Stable Antagonists of the Human α9α10 Nicotinic Acetylcholine Receptor for the Treatment of Neuropathic Pain

et al. 2021

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α9-Containing nicotinic acetylcholine receptors (nAChRs) are key targets for the treatment of neuropathic pain. α-Conotoxin RgIA4 is a peptide antagonist of human α9α10 nAChRs with high selectivity. However, structural rearrangement reveals a potential liability for clinical applications. We herein report our designer RgIA analogues stabilized by methylene thioacetal as nonopioid analgesic agents. We demonstrate that replacing disulfide loop I [CysI–CysIII] with methylene thioacetal in the RgIA skeleton results in activity loss, whereas substitution of loop II [CysII–CysIV] can be accommodated. The lead molecule, RgIA-5524, exhibits highly selective inhibition of α9α10 nAChRs with an IC50 of 0.9 nM and much reduced degradation in human serum. In vivo studies showed that RgIA-5524 relieves chemotherapy-induced neuropathic pain in wild type but not α9 knockout mouse models, demonstrating that α9-containing nAChRs are necessary for the therapeutic effects. This work highlights the application of methylene thioacetal as a disulfide surrogate in conotoxin-based, disulfide-rich peptide drugs.

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“…N -to- C -terminal backbone cyclization is another strategy that has received much attention in improving a peptide’s bioactivity and metabolic stability by constraining its conformational flexibility. − We therefore included a backbone cyclized analogue ([cyclic]-Linaclotide) in our structure–activity relationship (SAR) study.…”

Section: Resultsmentioning

confidence: 99%

Improving the Gastrointestinal Stability of Linaclotide

et al. 2021

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High susceptibility to proteolytic degradation in the gastrointestinal tract limits the therapeutic application of peptide drugs in gastrointestinal disorders. Linaclotide is an orally administered peptide drug for the treatment of irritable bowel syndrome with constipation (IBS-C) and abdominal pain. Linaclotide is however degraded in the intestinal environment within 1 h, and improvements in gastrointestinal stability might enhance its therapeutic application. We therefore designed and synthesized a series of linaclotide analogues employing a variety of strategic modifications and evaluated their gastrointestinal stability and pharmacological activity at its target receptor guanylate cyclase-C. All analogues had substantial improvements in gastrointestinal half-lives (>8 h vs linaclotide 48 min), and most remained active at low nanomolar concentrations. This work highlights strategic approaches for the development of gut-stable peptides toward the next generation of orally administered peptide drugs for the treatment of gastrointestinal disorders.

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Backbone Cyclization Turns a Venom Peptide into a Stable and Equipotent Ligand at Both Muscle and Neuronal Nicotinic Receptors

Cited by 13 publications

References 44 publications

Selective Agonists and Antagonists of α9 Versus α7 Nicotinic Acetylcholine Receptors

Selective Agonists and Antagonists of α9 Versus α7 Nicotinic Acetylcholine Receptors

Discovery of Methylene Thioacetal-Incorporated α-RgIA Analogues as Potent and Stable Antagonists of the Human α9α10 Nicotinic Acetylcholine Receptor for the Treatment of Neuropathic Pain

Improving the Gastrointestinal Stability of Linaclotide

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