Oligo-basic amino acids, potential nicotinic acetylcholine receptor inhibitors

Zhang, Baojian; Ren, Maomao; Yang, Fang; Li, Rui; Yu, Liutong; Luo, An; Zhangsun, Dongting; Luo, Sulan; Dong, Shuai

doi:10.1016/j.biopha.2022.113215

Cited by 4 publications

(4 citation statements)

References 58 publications

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“…The highest activity (in the nanomolar range) was observed for the hexadecaarginine peptide R16 and octaarginine R8, the latter being the most efficient against the α9α10 nAChR [ 95 ]. Recently, the action of a series of oligohistidines, oligolysines and oligoarginines was tested against nAChRs, oligoarginine R9 having a higher affinity than R8 toward α9α10 nAChRs [ 96 ]. Here, it should be noted that oligoarginines were known mainly as a means for the intracellular delivery of various compounds attached to them.…”

Section: α-Conotoxins In Distinguishing the Individual Nachr Subtypesmentioning

confidence: 99%

α7- and α9-Containing Nicotinic Acetylcholine Receptors in the Functioning of Immune System and in Pain

Shelukhina

Siniavin

Kasheverov

et al. 2023

IJMS

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Nicotinic acetylcholine receptors (nAChRs) present as many different subtypes in the nervous and immune systems, muscles and on the cells of other organs. In the immune system, inflammation is regulated via the vagus nerve through the activation of the non-neuronal α7 nAChR subtype, affecting the production of cytokines. The analgesic properties of α7 nAChR-selective compounds are mostly based on the activation of the cholinergic anti-inflammatory pathway. The molecular mechanism of neuropathic pain relief mediated by the inhibition of α9-containing nAChRs is not fully understood yet, but the role of immune factors in this process is becoming evident. To obtain appropriate drugs, a search of selective agonists, antagonists and modulators of α7- and α9-containing nAChRs is underway. The naturally occurring three-finger snake α-neurotoxins and mammalian Ly6/uPAR proteins, as well as neurotoxic peptides α-conotoxins, are not only sophisticated tools in research on nAChRs but are also considered as potential medicines. In particular, the inhibition of the α9-containing nAChRs by α-conotoxins may be a pathway to alleviate neuropathic pain. nAChRs are involved in the inflammation processes during AIDS and other viral infections; thus they can also be means used in drug design. In this review, we discuss the role of α7- and α9-containing nAChRs in the immune processes and in pain.

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Section: α-Conotoxins In Distinguishing the Individual Nachr Subtypesmentioning

confidence: 99%

α7- and α9-Containing Nicotinic Acetylcholine Receptors in the Functioning of Immune System and in Pain

Shelukhina

Siniavin

Kasheverov

et al. 2023

IJMS

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“…It was found that oligoarginines containing from 6 to 16 arginine residues (R6 to R16) interact with both muscle and neuronal nicotinic acetylcholine receptors (nAChRs), while the potency of inhibition of a particular receptor subtype depends on the peptide length ( Lebedev et al, 2019 ). Binding to nAChRs was studied not only for oligoarginines, but also for oligohistidines and oligolysines, and it was shown that oligoarginines of sufficient length are the most effective ( Zhang et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

“…Since a number of positively charged oligopeptides inhibit nAChRs ( Zhang et al, 2022 ), here we analyzed other low-molecular-mass polycationic compounds containing amino and guanidino groups. We started with biogenic polyamines putrescine (Put), spermidine (Spd), spermine (Spm), C -methylated Spm analogs, and agmatine (Agm) and its analogs ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of nicotinic acetylcholine receptors by oligoarginine peptides and polyamine-related compounds

Ojomoko,

Kryukova,

Egorova

et al. 2023

Front. Pharmacol.

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Oligoarginine peptides, known mostly for their cell-penetrating properties, are also inhibitors of the nicotinic acetylcholine receptors (nAChRs). Since octa-arginine (R8) inhibits α9α10 nAChR and suppresses neuropathic pain, we checked if other polycationic compounds containing amino and/or guanidino groups could be effective and tested the activity of the disulfide-fixed “cyclo”R8, a series of biogenic polyamines (putrescine, spermidine, and spermine), C-methylated spermine analogs, agmatine and its analogs, as well as acylpolyamine argiotoxin-636 from spider venom. Their inhibitory potency on muscle-type, α7 and α9α10 nAChRs was determined using radioligand analysis, electrophysiology, and calcium imaging. “Cyclo”R8 showed similar activity to that of R8 against α9α10 nAChR (IC50 ≈ 60 nM). Biogenic polyamines as well as agmatine and its analogs displayed low activity on muscle-type Torpedo californica, as well as α7 and α9α10 nAChRs, which increased with chain length, the most active being spermine and its C-methylated derivatives having IC50 of about 30 μM against muscle-type T. californica nAChR. Argiotoxin-636, which contains a polyamine backbone and terminal guanidino group, also weakly inhibited T. californica nAChR (IC50 ≈ 15 μM), but it revealed high potency against rat α9α10 nAChR (IC50 ≈ 200 nM). We conclude that oligoarginines and similar polycationic compounds effectively inhibiting α9α10 nAChR may serve as a basis for the development of analgesics to reduce neuropathic pain.

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“…The low-molecular-weight compounds (quaternary ammonium salts, alkaloids, heterocyclic compounds, etc.) [ 2 ], synthetic oligoarginine peptides [ 6 , 7 ] and venom peptides of various structural classes: three-finger toxins [ 3 , 8 ] and phospholipases A2 from snakes [ 2 , 9 ], α-conotoxins (α-CTx) [ 3 , 10 ], potassium channel scorpion toxins of α family (α-KTx) [ 11 ], toxin-like Ly6 [ 12 ] and C-type lectin-like proteins [ 2 ], were shown to act as agonists, antagonists, blockers, positive or negative allosteric modulators of distinct nAChR subtypes. The most investigated and numerous peptide modulators of nAChRs are snake three-finger α-neurotoxins and α-CTx [ 3 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Nicotinic Acetylcholine Receptors Are Novel Targets of APETx-like Toxins from the Sea Anemone Heteractis magnifica

Kalina

Kasheverov

Koshelev

et al. 2022

Toxins

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The nicotinic acetylcholine receptors (nAChRs) are prototypical ligand-gated ion channels, provide cholinergic signaling, and are modulated by various venom toxins and drugs in addition to neurotransmitters. Here, four APETx-like toxins, including two new toxins, named Hmg 1b-2 Metox and Hmg 1b-5, were isolated from the sea anemone Heteractis magnifica and characterized as novel nAChR ligands and acid-sensing ion channel (ASIC) modulators. All peptides competed with radiolabeled α-bungarotoxin for binding to Torpedo californica muscle-type and human α7 nAChRs. Hmg 1b-2 potentiated acetylcholine-elicited current in human α7 receptors expressed in Xenopus laevis oocytes. Moreover, the multigene family coding APETx-like peptides library from H. magnifica was described and in silico surface electrostatic potentials of novel peptides were analyzed. To explain the 100% identity of some peptide isoforms between H. magnifica and H. crispa, 18S rRNA, COI, and ITS analysis were performed. It has been shown that the sea anemones previously identified by morphology as H. crispa belong to the species H. magnifica.

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Oligo-basic amino acids, potential nicotinic acetylcholine receptor inhibitors

Cited by 4 publications

References 58 publications

α7- and α9-Containing Nicotinic Acetylcholine Receptors in the Functioning of Immune System and in Pain

α7- and α9-Containing Nicotinic Acetylcholine Receptors in the Functioning of Immune System and in Pain

Inhibition of nicotinic acetylcholine receptors by oligoarginine peptides and polyamine-related compounds

Nicotinic Acetylcholine Receptors Are Novel Targets of APETx-like Toxins from the Sea Anemone Heteractis magnifica

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