Structure–Function and Therapeutic Potential of Spider Venom-Derived Cysteine Knot Peptides Targeting Sodium Channels

Cardoso, Fernanda C.; Lewis, Richard J.

doi:10.3389/fphar.2019.00366

Cited by 48 publications

(45 citation statements)

References 87 publications

(162 reference statements)

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“…A recent 3D structure of a toxin-receptor complex is shown in Figure 3B. Most toxins were shown to bind to the helices S3 and S4 of the voltage sensing domain, allosterically modulating pore gating [137,138]. This is in contrast to the action of venom acylpolyamines, such as argiotoxin-636 (from Argiope lobata ), which inhibits calcium-permeable AMPA receptors by directly inserting into the pore [139].…”

Section: Spider Venom Compositionmentioning

confidence: 99%

Spider Venom: Components, Modes of Action, and Novel Strategies in Transcriptomic and Proteomic Analyses

Langenegger

Nentwig

Kuhn‐Nentwig

2019

Toxins

108

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This review gives an overview on the development of research on spider venoms with a focus on structure and function of venom components and techniques of analysis. Major venom component groups are small molecular mass compounds, antimicrobial (also called cytolytic, or cationic) peptides (only in some spider families), cysteine-rich (neurotoxic) peptides, and enzymes and proteins. Cysteine-rich peptides are reviewed with respect to various structural motifs, their targets (ion channels, membrane receptors), nomenclature, and molecular binding. We further describe the latest findings concerning the maturation of antimicrobial, and cysteine-rich peptides that are in most known cases expressed as propeptide-containing precursors. Today, venom research, increasingly employs transcriptomic and mass spectrometric techniques. Pros and cons of venom gland transcriptome analysis with Sanger, 454, and Illumina sequencing are discussed and an overview on so far published transcriptome studies is given. In this respect, we also discuss the only recently described cross contamination arising from multiplexing in Illumina sequencing and its possible impacts on venom studies. High throughput mass spectrometric analysis of venom proteomes (bottom-up, top-down) are reviewed.

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Section: Spider Venom Compositionmentioning

confidence: 99%

Spider Venom: Components, Modes of Action, and Novel Strategies in Transcriptomic and Proteomic Analyses

Langenegger

Nentwig

Kuhn‐Nentwig

2019

Toxins

108

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“…In the paper [50], information was gathered about the toxins inhibiting sodium channels and having an antinociceptive effect. The authors of [51] collected the data on cysteine knot peptides from spider venoms that modulate Nav and performed analysis of the structure–activity relationships of the compounds.…”

Section: Targets Of Analgesic and Antipruritic Therapymentioning

confidence: 99%

Psychotropic Drugs for the Management of Chronic Pain and Itch

Belinskaia

Barygin

et al. 2019

Pharmaceuticals

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Clinical observations have shown that patients with chronic neuropathic pain or itch exhibit symptoms of increased anxiety, depression and cognitive impairment. Such patients need corrective therapy with antidepressants, antipsychotics or anticonvulsants. It is known that some psychotropic drugs are also effective for the treatment of neuropathic pain and pruritus syndromes due to interaction with the secondary molecular targets. Our own clinical studies have identified antipruritic and/or analgesic efficacy of the following compounds: tianeptine (atypical tricyclic antidepressant), citalopram (selective serotonin reuptake inhibitor), mianserin (tetracyclic antidepressant), carbamazepine (anticonvulsant), trazodone (serotonin antagonist and reuptake inhibitor), and chlorprothixene (antipsychotic). Venlafaxine (serotonin-norepinephrine reuptake inhibitor) is known to have an analgesic effect too. The mechanism of such effect of these drugs is not fully understood. Herein we review and correlate the literature data on analgesic/antipruritic activity with pharmacological profile of these compounds.

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“…Several families of peptide toxins with extensive networks of cystine bridges have been isolated and characterized from natural sources (Lavergne et al, 2015). These highly constrained peptides with multiple disulfide bridges adopt very stable threedimensional structures, and as a result have highly specific and potent interactions with biological targets such as ion channels and GPCRs (Ferrat and Darbon, 2005;Akondi et al, 2014;Cardoso and Lewis, 2019). They are thus of significant interest to both pharmaceutical and academic groups, as potential therapeutic leads and as pharmacological probes (Norton, 2017), and one such toxin-derived structure, ziconotide (Prialt) is currently approved for the treatment of severe chronic pain (Schmidtko et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

A Chemical Biology Approach to Probing the Folding Pathways of the Inhibitory Cystine Knot (ICK) Peptide ProTx-II

McCarthy¹,

Robinson²,

Thalassinos

et al. 2020

Front. Chem.

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Peptide toxins that adopt the inhibitory cystine knot (ICK) scaffold have very stable three-dimensional structures as a result of the conformational constraints imposed by the configuration of the three disulfide bonds that are the hallmark of this fold. Understanding the oxidative folding pathways of these complex peptides, many of which are important therapeutic leads, is important in order to devise reliable synthetic routes to correctly folded, biologically active peptides. Previous research on the ICK peptide ProTx-II has shown that in the absence of an equilibrating redox buffer, misfolded intermediates form that prevent the formation of the native disulfide bond configuration. In this paper, we used tandem mass spectrometry to examine these misfolded peptides, and identified two non-native singly bridged peptides, one with a Cys(III)-Cys(IV) linkage and one with a Cys(V)-Cys(VI) linkage. Based on these results, we propose that the C-terminus of ProTx-II has an important role in initiating the folding of this peptide. To test this hypothesis, we have also studied the folding pathways of analogs of ProTx-II containing the disulfide-bond directing group penicillamine (Pen) under the same conditions. We find that placing Pen residues at the C-terminus of the ProTx-II analogs directs the folding pathway away from the singly bridged misfolded intermediates that represent a kinetic trap for the native sequence, and allows a fully oxidized final product to be formed with three disulfide bridges. However, multiple two-disulfide peptides were also produced, indicating that further study is required to fully control the folding pathways of this modified scaffold.

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Structure–Function and Therapeutic Potential of Spider Venom-Derived Cysteine Knot Peptides Targeting Sodium Channels

Cited by 48 publications

References 87 publications

Spider Venom: Components, Modes of Action, and Novel Strategies in Transcriptomic and Proteomic Analyses

Spider Venom: Components, Modes of Action, and Novel Strategies in Transcriptomic and Proteomic Analyses

Psychotropic Drugs for the Management of Chronic Pain and Itch

A Chemical Biology Approach to Probing the Folding Pathways of the Inhibitory Cystine Knot (ICK) Peptide ProTx-II

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