Spider-Venom Peptides as Therapeutics

Saez, Natalie J.; Senff, Sebastian; Jensen, Jonas E.; Er, Sing Yan; Herzig, Volker; Rash, Lachlan D.; King, Glenn F.

doi:10.3390/toxins2122851

Cited by 260 publications

(246 citation statements)

References 133 publications

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“…As a consequence they have attracted much interest as potential lead molecules for pharmaceutical development. 1,2 For lead optimisation, a detailed understanding of the interactions between the peptide and the ion channel is required. In recent years, the structures of several ion channels and some peptide-channel complexes have been solved experimentally in atomic detail, providing information on the precise manner in which certain peptides interact with specific ion channels.…”

Section: Introductionmentioning

confidence: 99%

Combination of Ambiguous and Unambiguous Data in the Restraint-driven Docking of Flexible Peptides with HADDOCK: The Binding of the Spider Toxin PcTx1 to the Acid Sensing Ion Channel (ASIC) 1a

Deplazes

Davies

Bonvin

et al. 2015

J. Chem. Inf. Model.

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Peptides that bind to ion channels have attracted much interest as potential lead molecules for the development of new drugs and insecticides. However, the structure determination of large peptidechannel complexes using experimental methods is challenging. Thus structural models are often derived from combining experimental information with restraint-driven docking approaches. Using the complex formed by the venom peptide PcTx1 and the acid sensing ion channel (ASIC) 1a as a case study, we have examined the effect of different combinations of restraints and input structures on the statistical likelihood of (a) correctly predicting the structure of the binding interface and (b) the ability to predict which residues are involved in specific pairwise peptide-channel interactions. For this, we have analyzed over 200 000 water-refined docked structures obtained with various amounts and types of restraints of the peptidechannel complex predicted using the docking program HADDOCK. We found that increasing the number of restraints or even the use of pairwise interaction data resulted in only a modest improvement in the likelihood of finding a structure within a given accuracy. This suggests that shape complementarity and the force field make a large contribution to the accuracy of the predicted structure. The results also showed that there are large variations in the accuracy of the predicted structure depending on the precise combination of residues used as restraints. Finally, we reflect on the limitations of relying on geometric criteria such as root-mean square deviations to assess the accuracy of docking procedures. We propose that in addition to currently used measures, the likelihood of finding a structure within a given level of accuracy should be also used to evaluate docking methods.

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Section: Introductionmentioning

confidence: 99%

Combination of Ambiguous and Unambiguous Data in the Restraint-driven Docking of Flexible Peptides with HADDOCK: The Binding of the Spider Toxin PcTx1 to the Acid Sensing Ion Channel (ASIC) 1a

Deplazes

Davies

Bonvin

et al. 2015

J. Chem. Inf. Model.

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“…VGSCs are essential to the initiation and propagation of electrical signals in the vertebrate nervous system, and aberrant sodium channel function is thought to underlie a variety of medical disorders, including epilepsy (10), arrhythmia (11), myotonia (12), and pain (13). VGSC-blocking spider toxins, therefore, may have significant therapeutic potential, and their detailed characterization is clearly warranted (14).…”

mentioning

confidence: 99%

“…Several of the best characterized peptides are from NaSpTx family 1. All peptides from this family were isolated from the venom of tarantulas (Theraphosidae), and they consist of [33][34][35] dues with three disulfide bridges that form an inhibitory cysteine knot (ICK) motif (14). Peptides from family 1 include huwentoxin-1 (/-TRTX-Hh1a) (16), hainantoxin-IV (-TRTXHhn1b) (9), phrixotoxin-3 (␤-TRTX-Ps1a) (5), ceratotoxin-1 (␤-TRTX-Cm1a) (5), and huwentoxin-4 (-TRTXHh2a, HwTX-IV) (8,17).…”

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confidence: 99%

Analysis of the Structural and Molecular Basis of Voltage-sensitive Sodium Channel Inhibition by the Spider Toxin Huwentoxin-IV (μ-TRTX-Hh2a)

Minassian¹,

Gibbs²,

Shih

et al. 2013

Journal of Biological Chemistry

139

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Background:The molecular basis for sodium channel inhibition by spider venom peptides is poorly understood. Results: Key toxin residues and structural features important for activity of huwentoxin-IV are identified. Conclusion: Toxin activity involves a hydrophobic protrusion surrounded by a ring of basic residues. Significance: New structure-function information may provide a foundation for the design of peptides with therapeutic potential.

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“…Of particular note, the biodiversity of oceanic islands is often underestimated [9]. In addition to the ecological impact of a decrease in snake species richness, these extinctions have economic consequences: venoms have applications in many fields including medicine, pharmacology and immunology [10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Vintage venoms: Proteomic and pharmacological stability of snake venoms stored for up to eight decades

Jesupret

Baumann

Jackson

et al. 2014

Journal of Proteomics

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For over a century, venom samples from wild snakes have been collected and stored around the world. However, the quality of storage conditions for "vintage" venoms has rarely been assessed. The goal of this study was to determine whether such historical venom samples are still biochemically and pharmacologically viable for research purposes, or if new sample efforts are needed. In total, 52 samples spanning 5 genera and 13 species with regional variants of some species (e.g., 14 different populations of Notechis scutatus) were analysed by a combined proteomic and pharmacological approach to determine protein structural stability and bioactivity. When venoms were not exposed to air during storage, the proteomic results were virtually indistinguishable from that of fresh venom and bioactivity was equivalent or only slightly reduced. By contrast, a sample of Acanthophis antarcticus venom that was exposed to air (due to a loss of integrity of the rubber stopper) suffered significant degradation as evidenced by the proteomics profile. Interestingly, the Keywords:Mass spectrometry Toxinology Stability studies These results demonstrate that with proper storage techniques, venom samples can retain structural and pharmacological stability. This article is part of a Special Issue entitled:Proteomics of non-model organisms. Biological significance• These results show that with proper storage venoms are useful for decades.• These results have direct implications for the use of rare venoms.

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Spider-Venom Peptides as Therapeutics

Cited by 260 publications

References 133 publications

Combination of Ambiguous and Unambiguous Data in the Restraint-driven Docking of Flexible Peptides with HADDOCK: The Binding of the Spider Toxin PcTx1 to the Acid Sensing Ion Channel (ASIC) 1a

Combination of Ambiguous and Unambiguous Data in the Restraint-driven Docking of Flexible Peptides with HADDOCK: The Binding of the Spider Toxin PcTx1 to the Acid Sensing Ion Channel (ASIC) 1a

Analysis of the Structural and Molecular Basis of Voltage-sensitive Sodium Channel Inhibition by the Spider Toxin Huwentoxin-IV (μ-TRTX-Hh2a)

Vintage venoms: Proteomic and pharmacological stability of snake venoms stored for up to eight decades

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