Antagonistic action on NMDA/GluN2B mediated currents of two peptides that were conantokin-G structure-based designed

Reyes-Guzmán, Edwin Alfredo; Castro, Nohora Angélica Vega; Reyes-Montaño, Edgar Antonio; Recio-Pinto, Esperanza

doi:10.1186/s12868-017-0361-4

Cited by 6 publications

(4 citation statements)

References 51 publications

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“…For example, 2‐Hydroxy‐5‐(2,3,5,6‐tetrafluoro‐4‐trifluoromethyl‐benzylamino)‐benzoic acid (Neu2000) is a GluN2B antagonist with multiple mechanisms and has a wide TTW (Section 2.1.5). Conantokin G (CGX‐1007) and its analog EAR16 is a polypeptide GluN2B antagonist with novel structure (Reyes‐Guzman et al., 2017). Intrathecal treatment with Conantokin‐G at 8 hr, but not at 10 or 12 hr, post‐occlusion significantly reduced infarct volume in tMCAO rats (Lu et al., 2005; Williams et al., 2002).…”

Section: Ttws Of Compounds Directly Acting On Nmda Receptorsmentioning

confidence: 99%

Therapeutic time windows of compounds against NMDA receptors signaling pathways for ischemic stroke

Huo

Xue

Niu

et al. 2021

J of Neuroscience Research

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Much evidence has proved that excitotoxicity induced by excessive release of glutamate contributes largely to damage caused by ischemia. In view of the key role played by NMDA receptors in mediating excitotoxicity, compounds against NMDA receptors signaling pathways have become the most promising type of anti‐stroke candidate compounds. However, the limited therapeutic time window for neuroprotection is a key factor preventing NMDA receptor‐related compounds from showing efficacy in all clinical trials for ischemic stroke. In this perspective, the determination of therapeutic time windows of these kinds of compounds is useful in ensuring a therapeutic effect and accelerating clinical application. This mini‐review discussed the therapeutic time windows of compounds against NMDA receptors signaling pathways, described related influence factors and the status of clinical studies. The purpose of this review is to look for compounds with wide therapeutic time windows and better clinical application prospect.

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Section: Ttws Of Compounds Directly Acting On Nmda Receptorsmentioning

confidence: 99%

Therapeutic time windows of compounds against NMDA receptors signaling pathways for ischemic stroke

Huo

Xue

Niu

et al. 2021

J of Neuroscience Research

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“…Gao et al [167] performed a homology search of Conus betulinus venoms to identify six sequences similar to α-ImI, of which two were demonstrated to have desirable insecticidal properties, while Barba et al [168] performed a sequence scan followed by MD simulations as the starting point for the design of an ω-GVIA mutant that strongly binds copper atoms to be used for environmental applications. Using conantokin-G as a starting sequence, Reyes-Guzman et al [169] employed docking studies to evaluate mutants and guide a search that resulted in two peptides (EAR16 and EAR18) that are capable of reversibly blocking the GluN2B NMDA receptor, which is implicated in neuronal function. Of particular note have been several studies that have developed novel methodologies while also utilizing them for design purposes.…”

Section: Computational Strategies To Understand and Predict Conopementioning

confidence: 99%

Snails In Silico: A Review of Computational Studies on the Conopeptides

et al. 2019

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Marine cone snails are carnivorous gastropods that use peptide toxins called conopeptides both as a defense mechanism and as a means to immobilize and kill their prey. These peptide toxins exhibit a large chemical diversity that enables exquisite specificity and potency for target receptor proteins. This diversity arises in terms of variations both in amino acid sequence and length, and in posttranslational modifications, particularly the formation of multiple disulfide linkages. Most of the functionally characterized conopeptides target ion channels of animal nervous systems, which has led to research on their therapeutic applications. Many facets of the underlying molecular mechanisms responsible for the specificity and virulence of conopeptides, however, remain poorly understood. In this review, we will explore the chemical diversity of conopeptides from a computational perspective. First, we discuss current approaches used for classifying conopeptides. Next, we review different computational strategies that have been applied to understanding and predicting their structure and function, from machine learning techniques for predictive classification to docking studies and molecular dynamics simulations for molecular-level understanding. We then review recent novel computational approaches for rapid high-throughput screening and chemical design of conopeptides for particular applications. We close with an assessment of the state of the field, emphasizing important questions for future lines of inquiry.

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“…κ-CTxs selection the voltage-sensitive K + channel are inhibited [4], while µ and µO-CTxs selectively act on the voltage-sensitive Na + channel [5][6][7]. In addition, some Conotoxins, which do not contain or contain a pair of disulfide bonds, can selectively act on vasopressin receptors (such as conopressin) [8], NMDA receptors (such as conantokins) [9], serotonin type 3 (5-HT3) receptors [10]. CTxs can distinguish and recognize many different subtypes or heterostructures of ion channels and neural receptors and are widely used in life science research; several CTxs have been marketed or entered clinical research as analgesics and antiepileptic drugs.…”

Section: Introductionmentioning

confidence: 99%

Structural and Functional Characterization of Conotoxins from Conus achatinus Targeting NMDAR

Liu¹,

Ge²,

Wang³

et al. 2020

Marine Drugs

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Conotoxin-Ac1 and its variant conotoxin-Ac1-O6P, were isolated from the venom duct of Conus achatinus, a fish-hunting cone snail species collected in the Sea of Hainan, China. Conotoxin-Ac1 is linear peptide that contain 15 amino acids. In the present study, we synthesized and structurally and functionally characterized conotoxin-Ac1 as well as 19 variants. Electrophysiological results showed that conotoxin-Ac1 inhibited N-methyl-D-aspartate receptor subunit 2B (NR2B) with an IC50 of 8.22 ± 0.022 μM. Further structure-activity studies of conotoxin-Ac demonstrated that polar amino acid residues were important for modulating its active, and the replacement of N1, O9, E10, and S12 by Ala resulted in a significant decrease in potency to NR2B. °Furthermore, conotoxin-Ac1 and conotoxin-Ac1-O6P were tested in hot-plate and tail-flick assays to measure the potential analgesic activity to an acute thermal stimulus in a dose-dependent manner. Subsequently, the analgesic activity of conotoxin-Ac1 mutants was analyzed by the hot-plate method. The results show that N1, Y2, Y3, E10, N11, S12, and T15 play an important role in the analgesic activity of conotoxin-Ac1. N1 and S12 have significant effects on conotoxin-Ac1 in inhibiting NR2B and analgesic activity. In conclusion, we have discovered that conotoxin-Ac1 is an inhibitor of NMDAR and displays antinociceptive activity.

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Antagonistic action on NMDA/GluN2B mediated currents of two peptides that were conantokin-G structure-based designed

Cited by 6 publications

References 51 publications

Therapeutic time windows of compounds against NMDA receptors signaling pathways for ischemic stroke

Therapeutic time windows of compounds against NMDA receptors signaling pathways for ischemic stroke

Snails In Silico: A Review of Computational Studies on the Conopeptides

Structural and Functional Characterization of Conotoxins from Conus achatinus Targeting NMDAR

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