Towards Structure-Guided Development of Pain Therapeutics Targeting Voltage-Gated Sodium Channels

Nguyen, Phuong T.; Yarov‐Yarovoy, Vladimir

doi:10.3389/fphar.2022.842032

Cited by 26 publications

(23 citation statements)

References 62 publications

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“…Thus, interactions between NaTx36 and OtNa V 1.8 provide a novel system for investigating links between activation – inactivation gating relationships, Na V channel availability, and mechanisms that inhibit Na V 1.8 activity and pain-related behavior. Moreover, NaTx36 may serve as a template for structure-guided development of Na V targeting peptides to treat pain without addiction ( Nguyen and Yarov-Yarovoy, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Structural and Functional Characterization of a Novel Scorpion Toxin that Inhibits NaV1.8 via Interactions With the DI Voltage Sensor and DII Pore Module

et al. 2022

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Voltage-gated sodium channel NaV1.8 regulates transmission of pain signals to the brain. While NaV1.8 has the potential to serve as a drug target, the molecular mechanisms that shape NaV1.8 gating are not completely understood, particularly mechanisms that couple activation to inactivation. Interactions between toxin producing animals and their predators provide a novel approach for investigating NaV structure-function relationships. Arizona bark scorpions produce Na+ channel toxins that initiate pain signaling. However, in predatory grasshopper mice, toxins inhibit NaV1.8 currents and block pain signals. A screen of synthetic peptide toxins predicted from bark scorpion venom showed that peptide NaTx36 inhibited Na+ current recorded from a recombinant grasshopper mouse NaV1.8 channel (OtNaV1.8). Toxin NaTx36 hyperpolarized OtNaV1.8 activation, steady-state fast inactivation, and slow inactivation. Mutagenesis revealed that the first gating charge in the domain I (DI) S4 voltage sensor and an acidic amino acid (E) in the DII SS2 – S6 pore loop are critical for the inhibitory effects of NaTx36. Computational modeling showed that a DI S1 – S2 asparagine (N) stabilizes the NaTx36 – OtNaV1.8 complex while residues in the DI S3 – S4 linker and S4 voltage sensor form electrostatic interactions that allow a toxin glutamine (Q) to contact the first S4 gating charge. Surprisingly, the models predicted that NaTx36 contacts amino acids in the DII S5 – SS1 pore loop instead of the SS2 – S6 loop; the DII SS2 – S6 loop motif (QVSE) alters the conformation of the DII S5 – SS1 pore loop, enhancing allosteric interactions between toxin and the DII S5 – SS1 pore loop. Few toxins have been identified that modify NaV1.8 gating. Moreover, few toxins have been described that modify sodium channel gating via the DI S4 voltage sensor. Thus, NaTx36 and OtNaV1.8 provide tools for investigating the structure-activity relationship between channel activation and inactivation gating, and the connection to alternative pain phenotypes.

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Section: Discussionmentioning

confidence: 99%

Structural and Functional Characterization of a Novel Scorpion Toxin that Inhibits NaV1.8 via Interactions With the DI Voltage Sensor and DII Pore Module

et al. 2022

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“…Peptide toxins have been essential molecular tools for studying the function, structure, and dynamics of ion channels for decades (Dutertre and Lewis, 2010; Herzig et al, 2020; Norton and Chandy, 2017). Moreover, they are promising biomolecules to develop biologics as therapeutics to target and modulate specific ion channels with superior subtype and state selectivity (Bordon et al, 2020; Neff and Wickenden, 2021; Nguyen and Yarov-Yarovoy, 2022; Norton, 2017; Norton and Chandy, 2017; Wulff et al, 2019). Limitations in obtaining high-resolution structural data to understand and harness the diverse molecular mechanisms of peptide toxins action on ion channels hamper the drug development process to optimize and translate these peptides to the clinic.…”

Section: Discussionmentioning

confidence: 99%

“…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). There is an immense diversity of venom peptides targeting ion channels (Herzig et al, 2020; Hung et al, 2017), and depending on resolving experimental structures of relevant toxins bound to their targets poses a bottleneck for our opportunities to exploit their potential for pre-clinical optimization and future clinical applications.…”

Section: Introductionmentioning

confidence: 99%

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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“…Voltage-gated sodium channels (Na V ) are critical molecular determinants of electrical impulses (action potentials) initiation and propagation, which underlie the electrical hyperexcitability characteristic of chronic inflammatory and neuropathic pain [ 51 , 52 ]. We have made in-depth research on the venom of the Chinese red-head centipede, Scolopendra subspinipes mutilans L. Koch.…”

Section: Centipede Toxins Acting On the Nervous Systemmentioning

confidence: 99%

Bioactive Peptides and Proteins from Centipede Venoms

et al. 2022

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Venoms are a complex cocktail of biologically active molecules, including peptides, proteins, polyamide, and enzymes widely produced by venomous organisms. Through long-term evolution, venomous animals have evolved highly specific and diversified peptides and proteins targeting key physiological elements, including the nervous, blood, and muscular systems. Centipedes are typical venomous arthropods that rely on their toxins primarily for predation and defense. Although centipede bites are frequently reported, the composition and effect of centipede venoms are far from known. With the development of molecular biology and structural biology, the research on centipede venoms, especially peptides and proteins, has been deepened. Therefore, we summarize partial progress on the exploration of the bioactive peptides and proteins in centipede venoms and their potential value in pharmacological research and new drug development.

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Towards Structure-Guided Development of Pain Therapeutics Targeting Voltage-Gated Sodium Channels

Cited by 26 publications

References 62 publications

Structural and Functional Characterization of a Novel Scorpion Toxin that Inhibits NaV1.8 via Interactions With the DI Voltage Sensor and DII Pore Module

Structural and Functional Characterization of a Novel Scorpion Toxin that Inhibits NaV1.8 via Interactions With the DI Voltage Sensor and DII Pore Module

Structural Modeling of Peptide Toxin - Ion Channel Interactions using RosettaDock

Bioactive Peptides and Proteins from Centipede Venoms

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