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      Centipede Venom Peptides Acting on Ion Channels

      review-article
      Author(s): 1 , 2 , 3 , 4 , * , 1 , 2 , 3 , 4 , 1 , 2 , 3 , *
      Publication date (Electronic):
      Journal: Toxins
      Publisher: MDPI
      Keywords: animal toxin, ion channel, centipede venom, drug discovery, peptide drug

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          Abstract

          Centipedes are among the oldest venomous arthropods that use their venom to subdue the prey. The major components of centipede venom are a variety of low-molecular-weight peptide toxins that have evolved to target voltage-gated ion channels to interfere with the central system of prey and produce pain or paralysis for efficient hunting. Peptide toxins usually contain several intramolecular disulfide bonds, which confer chemical, thermal and biological stability. In addition, centipede peptides generally have novel structures and high potency and specificity and therefore hold great promise both as diagnostic tools and in the treatment of human disease. Here, we review the centipede peptide toxins with reported effects on ion channels, including Nav, Kv, Cav and the nonselective cation channel polymodal transient receptor potential vanilloid 1 (TRPV1).

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          TRPV1 structures in distinct conformations reveal mechanisms of activation

          Erhu Cao, Maofu Liao, Yifan Cheng … (2013)
          TRP channels are polymodal signal detectors that respond to a wide range of physical and chemical stimuli. Elucidating how these channels integrate and convert physiological signals into channel opening is essential to understanding how they regulate cell excitability under normal and pathophysiological conditions. Here we exploit pharmacological probes (a peptide toxin and small vanilloid agonists) to determine structures of two activated states of the capsaicin receptor, TRPV1. A domain (S1-S4) that moves during activation of voltage-gated channels remains stationary in TRPV1, highlighting differences in gating mechanisms for these structurally related channel superfamilies. TRPV1 opening is associated with major structural rearrangements in the outer pore, including the pore helix and selectivity filter, as well as pronounced dilation of a hydrophobic constriction at the lower gate, suggesting a dual gating mechanism. Allosteric coupling between upper and lower gates may account for rich physiologic modulation exhibited by TRPV1 and other TRP channels.
          Article 0 comments Cited 377 times – based on 0 reviews     Review now
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            Venoms as a platform for human drugs: translating toxins into therapeutics.

            Glenn King (2011)
            An extraordinarily diverse range of animals have evolved venoms for predation, defence, or competitor deterrence. The major components of most venoms are peptides and proteins that are often protease-resistant due to their disulfide-rich architectures. Some of these toxins have become valuable as pharmacological tools and/or therapeutics due to their extremely high specificity and potency for particular molecular targets. There are currently six FDA-approved drugs derived from venom peptides or proteins. This article surveys the current pipeline of venom-derived therapeutics and critically examines the potential of peptide and protein drugs derived from venoms. Emerging trends are identified, including an increasing industry focus on disulfide-rich venom peptides and the use of a broader array of molecular targets in order to develop venom-based therapeutics for treating a wider range of clinical conditions. Key technical advances in combination with a renewed industry-wide focus on biologics have converged to provide a larger than ever pipeline of venom-derived therapeutics. Disulfide-rich venom peptides obviate some of the traditional disadvantages of therapeutic peptides and some may be suitable for oral administration. Moreover, some venom peptides can breach the blood brain barrier and translocate across cell membranes, which opens up the possibility of exploiting molecular targets not previously accessible to peptide drugs.
            Article 0 comments Cited 168 times – based on 0 reviews     Review now
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              Acid potentiation of the capsaicin receptor determined by a key extracellular site.

              S E Jordt, M Tominaga, D Julius (2000)
              The capsaicin (vanilloid) receptor, VR1, is a sensory neuron-specific ion channel that serves as a polymodal detector of pain-producing chemical and physical stimuli. The response of VR1 to capsaicin or noxious heat is dynamically potentiated by extracellular protons within a pH range encountered during tissue acidosis, such as that associated with arthritis, infarction, tumor growth, and other forms of injury. A molecular determinant for this important physiological activity was localized to an extracellular Glu residue (E600) in the region linking the fifth transmembrane domain with the putative pore-forming region of the channel. We suggest that this residue serves as a key regulatory site of the receptor by setting sensitivity to other noxious stimuli in response to changes in extracellular proton concentration. We also demonstrate that protons, vanilloids, and heat promote channel opening through distinct pathways, because mutations at a second site (E648) selectively abrogate proton-evoked channel activation without diminishing responses to other noxious stimuli. Our findings provide molecular evidence for stimulus-specific steps in VR1 activation and offer strategies for the development of novel analgesic agents.
              Article 0 comments Cited 156 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Toxins (Basel)
                Journal ID (iso-abbrev): Toxins (Basel)
                Journal ID (publisher-id): toxins
                Title: Toxins
                Publisher: MDPI
                ISSN (Electronic): 2072-6651
                Publication date (Electronic): 05 April 2020
                Publication date Collection: April 2020
                Volume: 12
                Issue: 4
                Electronic Location Identifier: 230
                Affiliations
                [1 ]School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China; grfqiupeiju@ 123456hotmail.com
                [2 ]Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266003, China
                [3 ]Innovation Center for Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266003, China
                [4 ]Marine Biomedical Research Institute of Qingdao, Qingdao 266071, China
                Author notes
                [* ]Correspondence: chuyanyan@ 123456ouc.edu.cn (Y.C.); ryu@ 123456ouc.edu.cn (R.Y.)
                Author information
                https://orcid.org/0000-0001-6625-2014
                Article
                Publisher ID: toxins-12-00230
                DOI: 10.3390/toxins12040230
                PMC ID: 7232367
                PubMed ID: 32260499
                SO-VID: 5f223bff-9edf-468e-be0d-92a954f58240
                Copyright © © 2020 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 01 March 2020
                Date accepted : 01 April 2020
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular medicine
                Keywords: animal toxin,ion channel,centipede venom,drug discovery,peptide drug
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: animal toxin, ion channel, centipede venom, drug discovery, peptide drug

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