Selective Targeting of Nav1.7 with Engineered Spider Venom-Based Peptides

Neff, Robert A.; Wickenden, Alan D.

doi:10.1080/19336950.2020.1860382

Cited by 14 publications

(24 citation statements)

References 82 publications

(68 reference statements)

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“…Huwentoxin-IV (HWTX-IV) and Protoxin-II (ProTx-II) from tarantula venom are peptide toxins that have subtype selectivity for and state-dependent antagonist activity against human Na V 1.7 channel (Schmalhofer et al, 2008; Xiao et al, 2010) that play a key role in the transmission of pain signals (Bennett et al, 2019). HWTX-IV and ProTx-II peptides have been used as scaffolds for optimization of peptides targeting NaV1.7 to develop novel therapeutics to treat pain (Adams et al, 2022; Flinspach et al, 2017; Jiang et al, 2021c; Lawrence et al, 2019; Neff and Wickenden, 2021; Neff et al, 2020). ProTx-II and HWTX-IV inhibit activation of Na V 1.7 by trapping the VSDII in a deactivated state (IC 50 ∼ 1 nM for ProTx-II and ∼20 nM for HWTX-IV) (Park et al, 2014; Peng et al, 2002; Schmalhofer et al, 2008; Sokolov et al, 2008; Xiao et al, 2010, 2011; Xu et al, 2019).…”

Section: Resultsmentioning

confidence: 99%

“…The therapeutic potential of animal toxins has already been harnessed (Bordon et al, 2020; Muttenthaler et al, 2021; Pennington et al, 2018), resulting in unique treatments like ziconotide for the treatment of severe chronic pain (McGivern, 2007) or the lizard-derived toxin exenatide for the treatment of treat type 2 diabetes (Holz and Chepurny, 2003). However, enhancement of the native peptide toxins to better fulfill their therapeutic effects has proven difficult and expensive (Neff and Wickenden, 2021). When atomistic peptide – ion channel structures are available, structure-guided computational design can be used to improve the binding features of the peptide, boosting the drug development process (Nguyen and Yarov-Yarovoy, 2022).…”

Section: Introductionmentioning

confidence: 99%

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Structural Modeling of Peptide Toxin - Ion Channel Interactions using RosettaDock

Mateos

Yarov‐Yarovoy

2022

Preprint

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Voltage-gated ion channels play essential physiological roles in action potential generation and propagation. Peptidic toxins from animal venoms target ion channels and provide useful scaffolds for the rational design of novel channel modulators with enhanced potency and subtype selectivity. Despite recent progress in obtaining experimental structures of peptide toxin – ion channel complexes, structural determination of peptide toxins bound to ion channels in physiologically important states remains challenging. Here we describe an application of RosettaDock approach to structural modeling of peptide toxins interactions with ion channels. We tested this approach on 10 structures of peptide toxin – ion channel complexes and demonstrated that it can sample near-native structures in all tested cases. Our approach will be useful for improving understanding of the molecular mechanism of natural peptide toxin modulation of ion channel gating and for the structural modeling of novel peptide-based ion channel modulators.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structural Modeling of Peptide Toxin - Ion Channel Interactions using RosettaDock

Mateos

Yarov‐Yarovoy

2022

Preprint

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“…Some limitations of using venom toxins and peptides as drug leads exist, such as limited membrane permeability and therefore reduced bioavailability for humans, as well as poor in vivo stability and fast clearance ( Otvos and Wade, 2014 ; Lau and Dunn, 2018 ). Where native wild-type toxins fall short of the strict activity or selectivity requirements for a drug, “toxineering” approaches (rational engineering of the toxin sequence) may be employed to improve drug properties and minimize off-target activity ( Gui et al, 2014 ; Klint et al, 2015 ; Neff and Wickenden, 2021 ), which has already led to several animal-toxin-derived drugs on the market ( Table 2 ).…”

Section: Applications Derived From Recombinantly Expressed Toxinsmentioning

confidence: 99%

Strategies for Heterologous Expression, Synthesis, and Purification of Animal Venom Toxins

Rivera-de-Torre

Rimbault

Jenkins

et al. 2022

Front. Bioeng. Biotechnol.

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Animal venoms are complex mixtures containing peptides and proteins known as toxins, which are responsible for the deleterious effect of envenomations. Across the animal Kingdom, toxin diversity is enormous, and the ability to understand the biochemical mechanisms governing toxicity is not only relevant for the development of better envenomation therapies, but also for exploiting toxin bioactivities for therapeutic or biotechnological purposes. Most of toxinology research has relied on obtaining the toxins from crude venoms; however, some toxins are difficult to obtain because the venomous animal is endangered, does not thrive in captivity, produces only a small amount of venom, is difficult to milk, or only produces low amounts of the toxin of interest. Heterologous expression of toxins enables the production of sufficient amounts to unlock the biotechnological potential of these bioactive proteins. Moreover, heterologous expression ensures homogeneity, avoids cross-contamination with other venom components, and circumvents the use of crude venom. Heterologous expression is also not only restricted to natural toxins, but allows for the design of toxins with special properties or can take advantage of the increasing amount of transcriptomics and genomics data, enabling the expression of dormant toxin genes. The main challenge when producing toxins is obtaining properly folded proteins with a correct disulfide pattern that ensures the activity of the toxin of interest. This review presents the strategies that can be used to express toxins in bacteria, yeast, insect cells, or mammalian cells, as well as synthetic approaches that do not involve cells, such as cell-free biosynthesis and peptide synthesis. This is accompanied by an overview of the main advantages and drawbacks of these different systems for producing toxins, as well as a discussion of the biosafety considerations that need to be made when working with highly bioactive proteins.

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“…The mutant peptide also provides analgesia in a mouse model of acute pain confirming the same in vivo activity as the wild type peptide. Such mutations were done on several spider toxins allowing more selective and potent Nav1.7 antagonists [ 331 ].…”

Section: Toxins As a Basis For Developing New Pain Treatmentsmentioning

confidence: 99%

Pain-related toxins in scorpion and spider venoms: a face to face with ion channels

Diochot

2021

J. Venom. Anim. Toxins incl. Trop. Dis

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Pain is a common symptom induced during envenomation by spiders and scorpions. Toxins isolated from their venom have become essential tools for studying the functioning and physiopathological role of ion channels, as they modulate their activity. In particular, toxins that induce pain relief effects can serve as a molecular basis for the development of future analgesics in humans. This review provides a summary of the different scorpion and spider toxins that directly interact with pain-related ion channels, with inhibitory or stimulatory effects. Some of these toxins were shown to affect pain modalities in different animal models providing information on the role played by these channels in the pain process. The close interaction of certain gating-modifier toxins with membrane phospholipids close to ion channels is examined along with molecular approaches to improve selectivity, affinity or bioavailability in vivo for therapeutic purposes.

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Selective Targeting of Nav1.7 with Engineered Spider Venom-Based Peptides

Cited by 14 publications

References 82 publications

Structural Modeling of Peptide Toxin - Ion Channel Interactions using RosettaDock

Structural Modeling of Peptide Toxin - Ion Channel Interactions using RosettaDock

Strategies for Heterologous Expression, Synthesis, and Purification of Animal Venom Toxins

Pain-related toxins in scorpion and spider venoms: a face to face with ion channels

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