µ-Conotoxins Modulating Sodium Currents in Pain Perception and Transmission: A Therapeutic Potential

Tosti, Elisabetta; Boni, Raffaele; Gallo, Alessandra

doi:10.3390/md15100295

Cited by 27 publications

(20 citation statements)

References 97 publications

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“…These venom components are commonly named conotoxins, a unique and remarkably diverse group of bioactive peptides with various pharmacological functions [6,14,15,16,17], which target a wide variety of ion channels, receptors, and even their subtypes in preys, predators, and humans with high affinity and specificity [6,18,19,20]. Consequently, conotoxins have become a research hotspot for the treatment of various neuropathic diseases, such as neuralgia, epilepsy, addiction, and Parkinson’s disease [6,21,22,23,24,25,26,27,28,29,30,31].…”

Section: Introductionmentioning

confidence: 99%

High-Throughput Identification and Analysis of Novel Conotoxins from Three Vermivorous Cone Snails by Transcriptome Sequencing

Ge¹,

Peng

Zhu

et al. 2019

Marine Drugs

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The venom of each Conus species consists of a diverse array of neurophysiologically active peptides, which are mostly unique to the examined species. In this study, we performed high-throughput transcriptome sequencing to extract and analyze putative conotoxin transcripts from the venom ducts of 3 vermivorous cone snails (C. caracteristicus, C. generalis, and C. quercinus), which are resident in offshore waters of the South China Sea. In total, 118, 61, and 48 putative conotoxins (across 22 superfamilies) were identified from the 3 Conus species, respectively; most of them are novel, and some possess new cysteine patterns. Interestingly, a series of 45 unassigned conotoxins presented with a new framework of C-C-C-C-C-C, and their mature regions were sufficiently distinct from any other known conotoxins, most likely representing a new superfamily. O- and M-superfamily conotoxins were the most abundant in transcript number and transcription level, suggesting their critical roles in the venom functions of these vermivorous cone snails. In addition, we identified numerous functional proteins with potential involvement in the biosynthesis, modification, and delivery process of conotoxins, which may shed light on the fundamental mechanisms for the generation of these important conotoxins within the venom duct of cone snails.

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Section: Introductionmentioning

confidence: 99%

High-Throughput Identification and Analysis of Novel Conotoxins from Three Vermivorous Cone Snails by Transcriptome Sequencing

Ge¹,

Peng

Zhu

et al. 2019

Marine Drugs

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“…Thus, conotoxins have potentially wide applications in the fields of neuroscience research and development. Many conotoxins are proving to be valuable as research tools, drug leads, and drugs [ 14 , 15 , 77 ]. We performed a detailed survey of US patent literature covering conotoxins to determine their potential therapeutic applications.…”

Section: Recent Advances In Conotoxins For Drug Developmentmentioning

confidence: 99%

Cone Snails: A Big Store of Conotoxins for Novel Drug Discovery

Gao

Peng

Yang³

et al. 2017

Toxins

106

113

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Marine drugs have developed rapidly in recent decades. Cone snails, a group of more than 700 species, have always been one of the focuses for new drug discovery. These venomous snails capture prey using a diverse array of unique bioactive neurotoxins, usually named as conotoxins or conopeptides. These conotoxins have proven to be valuable pharmacological probes and potential drugs due to their high specificity and affinity to ion channels, receptors, and transporters in the nervous systems of target prey and humans. Several research groups, including ours, have examined the venom gland of cone snails using a combination of transcriptomic and proteomic sequencing, and revealed the existence of hundreds of conotoxin transcripts and thousands of conopeptides in each Conus species. Over 2000 nucleotide and 8000 peptide sequences of conotoxins have been published, and the number is still increasing quickly. However, more than 98% of these sequences still lack 3D structural and functional information. With the rapid development of genomics and bioinformatics in recent years, functional predictions and investigations on conotoxins are making great progress in promoting the discovery of novel drugs. For example, ω-MVIIA was approved by the U.S. Food and Drug Administration in 2004 to treat chronic pain, and nine more conotoxins are at various stages of preclinical or clinical evaluation. In short, the genus Conus, the big family of cone snails, has become an important genetic resource for conotoxin identification and drug development.

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“…For example, these small proteins (10–50 amino acids) are of interest in the area of drug design (e.g., for the fabrication of pain killers). Studying their folding behavior and applications is an active field of research [TTO*12, TBG17]. MD simulations may contain several hundreds of thousands of time‐steps, each representing the conformation of the molecule in a folding process.…”

Section: Requirementsmentioning

confidence: 99%

Analyzing Residue Surface Proximity to Interpret Molecular Dynamics

Lichtenberg

Menges

Ageev

et al. 2018

Computer Graphics Forum

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Figure 1: From an input molecule (left), we derive a surface proximity term (center, left) that represents the closeness of an atom to the molecule surface. We apply this method to a Molecular Dynamics simulation to obtain a color-coded map, representing the trajectory for each atom or residue (center). Single time-steps can be visualized in 3D (right), e.g., VdW-spheres or in a combined backbone-helix form. AbstractThe surface of a molecule holds important information about the interaction behavior with other molecules. In dynamic folding or docking processes, residues of amino acids with different properties change their position within the molecule over time. The atoms of the residues that are accessible to the solvent can directly contribute to binding interactions, while residues buried within the molecular structure contribute to the stability of the molecule. Understanding patterns and causality of structural changes is important for experts in the pharmaceutical domain, e.g., in the process of drug design. We apply an iterative computation of the Solvent Accessible Surface in order to extract virtual layers of a molecule. The extraction allows to track the movement of residues in the body of the molecule, with respect to the distance of the residue to the surface or the core during dynamics simulations. We visualize the obtained layer information for the complete time span of the molecular dynamics simulation as a 2D-map and for individual time-steps as a 3D-representation of the molecule. The data acquisition has been implemented alongside with further analysis functionality in a prototypical application, which is available to the public domain. We underline the feasibility of our approach with a study from the pharmaceutical domain, where our approach has been used for novel insights into the folding behavior of µ-conotoxins.

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µ-Conotoxins Modulating Sodium Currents in Pain Perception and Transmission: A Therapeutic Potential

Cited by 27 publications

References 97 publications

High-Throughput Identification and Analysis of Novel Conotoxins from Three Vermivorous Cone Snails by Transcriptome Sequencing

High-Throughput Identification and Analysis of Novel Conotoxins from Three Vermivorous Cone Snails by Transcriptome Sequencing

Cone Snails: A Big Store of Conotoxins for Novel Drug Discovery

Analyzing Residue Surface Proximity to Interpret Molecular Dynamics

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