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Antibodies and venom peptides: new modalities for ion channels

Nature Reviews Drug Discovery volume 18, pages 339–357 (2019)Cite this article

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Abstract

Ion channels play fundamental roles in both excitable and non-excitable tissues and therefore constitute attractive drug targets for myriad neurological, cardiovascular and metabolic diseases as well as for cancer and immunomodulation. However, achieving selectivity for specific ion channel subtypes with small-molecule drugs has been challenging, and there currently is a growing trend to target ion channels with biologics. One approach is to improve the pharmacokinetics of existing or novel venom-derived peptides. In parallel, after initial studies with polyclonal antibodies demonstrated the technical feasibility of inhibiting channel function with antibodies, multiple preclinical programmes are now using the full spectrum of available technologies to generate conventional monoclonal and engineered antibodies or nanobodies against extracellular loops of ion channels. After a summary of the current state of ion channel drug discovery, this Review discusses recent developments using the purinergic receptor channel P2X purinoceptor 7 (P2X7), the voltage-gated potassium channel KV1.3 and the voltage-gated sodium channel NaV1.7 as examples of targeting ion channels with biologics.

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Fig. 1: Small molecules targeting ion channels.
Fig. 2: Structures of peptide toxins targeting ion channels.
Fig. 3: Antibodies and antibody derivatives being investigated to target ion channels.

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References

  1. Alexander, S. P. et al. THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: overview. Br. J. Pharmacol. 174 (Suppl. 1), S1–S16 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Alexander, S. P. et al. THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: voltage-gated ion channels. Br. J. Pharmacol. 174 (Suppl. 1), S160–S194 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Alexander, S. P. et al. THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: ligand-gated ion channels. Br. J. Pharmacol. 174 (Suppl. 1), S130–S159 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Alexander, S. P. et al. THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: other ion channels. Br. J. Pharmacol. 174 (Suppl. 1), S195–S207 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Santos, R. et al. A comprehensive map of molecular drug targets. Nat. Rev. Drug Discov. 16, 19–34 (2017).

    CAS  PubMed  Google Scholar 

  6. Sakmann, B. & Neher, E. Patch clamp techniques for studying ionic channels in excitable membranes. Ann. Rev. Physiol. 46, 455–472 (1984).

    CAS  Google Scholar 

  7. Hille, B. Ionic Channels Of Excitable Membranes 2nd edn (Sinauer Associates, 1992).

  8. Hille, B. Ion Channels Of Excitable Membranes 3rd edn (Sinauer Associates, 2001).

  9. Kaczorowski, G. J., McManus, O. B., Priest, B. T. & Garcia, M. L. Ion channels as drug targets: the next GPCRs. J. Gen. Physiol. 131, 399–405 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Wulff, H., Castle, N. A. & Pardo, L. A. Voltage-gated potassium channels as therapeutic targets. Nat. Rev. Drug Discov. 8, 982–1001 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Patapoutian, A., Tate, S. & Woolf, C. J. Transient receptor potential channels: targeting pain at the source. Nat. Rev. Drug Discov. 8, 55–68 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Verkman, A. S. & Galietta, L. J. Chloride channels as drug targets. Nat. Rev. Drug Discov. 8, 153–171 (2009).

    CAS  PubMed  Google Scholar 

  13. Zamponi, G. W. Targeting voltage-gated calcium channels in neurological and psychiatric diseases. Nat. Rev. Drug Discov. 15, 19–34 (2016).

    CAS  PubMed  Google Scholar 

  14. Bennett, P. B. & Guthrie, H. R. Trends in ion channel drug discovery: advances in screening technologies. Trends Biotechnol. 21, 563–569 (2003).

    CAS  PubMed  Google Scholar 

  15. Dunlop, J., Bowlby, M., Peri, R., Vasilyev, D. & Arias, R. High-throughput electrophysiology: an emerging paradigm for ion-channel screening and physiology. Nat. Rev. Drug Discov. 7, 358–368 (2008).

    CAS  PubMed  Google Scholar 

  16. Goodman, A. D. et al. Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial. Lancet 373, 732–738 (2009).

    CAS  PubMed  Google Scholar 

  17. Vilaine, J. P. The discovery of the selective If current inhibitor ivabradine. A new therapeutic approach to ischemic heart disease. Pharmacol. Res. 53, 424–434 (2006).

    CAS  PubMed  Google Scholar 

  18. Van Goor, F. et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc. Natl Acad. Sci. USA 106, 18825–18830 (2009). This study describes the discovery of the CFTR potentiator VX-770, which would eventually become ivacaftor.

    PubMed  PubMed Central  Google Scholar 

  19. Hutchings, C. J., Koglin, M., Olson, W. C. & Marshall, F. H. Opportunities for therapeutic antibodies directed at G-protein-coupled receptors. Nat. Rev. Drug Discov. 16, 787–810 (2017).

    CAS  PubMed  Google Scholar 

  20. Hann, M. M. & Keseru, G. M. Finding the sweet spot: the role of nature and nurture in medicinal chemistry. Nat. Rev. Drug Discov. 11, 355–365 (2012).

    CAS  PubMed  Google Scholar 

  21. Stepan, A. F. et al. Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: a perspective based on the critical examination of trends in the top 200 drugs marketed in the United States. Chem. Res. Toxicol. 24, 1345–1410 (2011).

    CAS  PubMed  Google Scholar 

  22. Catterall, W. A. Voltage-gated sodium channels at 60: structure, function and pathophysiology. J. Physiol. 590, 2577–2589 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Catterall, W. A. Forty years of sodium channels: structure, function, pharmacology, and epilepsy. Neurochem. Res. 42, 2495–2504 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Osteen, J. D. et al. Selective spider toxins reveal a role for the NaV1.1 channel in mechanical pain. Nature 534, 494–499 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Salvatierra, J. et al. NaV1.1 inhibition can reduce visceral hypersensitivity. JCI Insight 3, 121000 (2018).

    PubMed  Google Scholar 

  26. de Lera Ruiz, M. & Kraus, R. L. Voltage-gated sodium channels: structure, function, pharmacology, and clinical indications. J. Med. Chem. 58, 7093–7118 (2015).

    PubMed  Google Scholar 

  27. Cox, J. J. et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature 444, 894–898 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Cummins, T. R., Dib-Hajj, S. D. & Waxman, S. G. Electrophysiological properties of mutant NaV1.7 sodium channels in a painful inherited neuropathy. J. Neurosci. 24, 8232–8236 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Faber, C. G. et al. Gain-of-function NaV1.8 mutations in painful neuropathy. Proc. Natl Acad. Sci. USA 109, 19444–19449 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Feller, L., Khammissa, R. A. G., Fourie, J., Bouckaert, M. & Lemmer, J. Postherpetic neuralgia and trigeminal neuralgia. Pain Res. Treat. 2017, 1681765 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Ahuja, S. et al. Structural basis of NaV1.7 inhibition by an isoform-selective small-molecule antagonist. Science 350, aac5464 (2015). This paper shows a hybrid bacterial–human Na V structure detailing the receptor site of the aryl sulfonamides in the voltage sensor domain and provides an explanation for their Na V 1.7 selectivity.

    PubMed  Google Scholar 

  32. Alexandrou, A. J. et al. Subtype-selective small molecule inhibitors reveal a fundamental role for NaV1.7 in nociceptor electrogenesis, axonal conduction and presynaptic release. PLOS ONE 11, e0152405 (2016).

    PubMed  PubMed Central  Google Scholar 

  33. Kornecook, T. J. et al. Pharmacologic characterization of AMG8379, a potent and selective small molecule sulfonamide antagonist of the voltage-gated sodium channel NaV1.7. J. Pharmacol. Exp. Ther. 362, 146–160 (2017).

    CAS  PubMed  Google Scholar 

  34. McDonnell, A. et al. Efficacy of the NaV1.7 blocker PF-05089771 in a randomised, placebo-controlled, double-blind clinical study in subjects with painful diabetic peripheral neuropathy. Pain 159, 1465–1476 (2018).

    CAS  PubMed  Google Scholar 

  35. Focken, T. et al. Design of conformationally constrained acyl sulfonamide isosteres: identification of N-([1,2,4]triazolo[4,3-a]pyridin-3-yl)methane-sulfonamides as potent and selective hNaV1.7 inhibitors for the treatment of pain. J. Med. Chem. 61, 4810–4831 (2018).

    CAS  PubMed  Google Scholar 

  36. Bankar, G. et al. Selective NaV1.7 antagonists with long residence time show improved efficacy against inflammatory and neuropathic pain. Cell Rep. 24, 3133–3145 (2018).

    CAS  PubMed  Google Scholar 

  37. Casula, M. A. et al. Expression of the sodium channel β3 subunit in injured human sensory neurons. Neuroreport 15, 1629–1632 (2004).

    CAS  PubMed  Google Scholar 

  38. Berta, T. et al. Transcriptional and functional profiles of voltage-gated Na+ channels in injured and non-injured DRG neurons in the SNI model of neuropathic pain. Mol. Cell. Neurosci. 37, 196–208 (2008).

    CAS  PubMed  Google Scholar 

  39. Sokolov, M. V. et al. Co-expression of β-subunits with the voltage-gated sodium channel NaV1.7: the importance of subunit association and phosphorylation and their effects on channel pharmacology and biophysics. J. Mol. Neurosci. 65, 154–166 (2018).

    CAS  PubMed  Google Scholar 

  40. Yan, Z. et al. Structure of the NaV1.4-β1 complex from electric eel. Cell 170, 470–482 (2017).

    CAS  PubMed  Google Scholar 

  41. Pan, X. et al. Structure of the human voltage-gated sodium channel NaV1.4 in complex with β1. Science 362, 6412 (2018). This study describes the first cryoelectron microscopy structure of a human voltage-gated sodium channel at 3.2 Å resolution.

    Google Scholar 

  42. Deuis, J. R. et al. Analgesic effects of GpTx-1, PF-04856264 and CNV1014802 in a mouse model of NaV1.7-mediated pain. Toxins (Basel) 8, E78 (2016).

    Google Scholar 

  43. Sanguinetti, M. C. & Tristani-Firouzi, M. hERG potassium channels and cardiac arrhythmia. Nature 440, 463–469 (2006).

    CAS  PubMed  Google Scholar 

  44. Wang, W. & MacKinnon, R. Cryo-EM structure of the open human ether-a-go-go-related K+ channel hERG. Cell 169, 422–430 (2017). This study describes the cryoelectron microscopy structure of the hERG channel, probably the most famous off-target.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Vandenberg, J. I., Perozo, E. & Allen, T. W. Towards a structural view of drug binding to hERG K+ channels. Trends Pharmacol. Sci. 38, 899–907 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Casida, J. E. & Durkin, K. A. Neuroactive insecticides: targets, selectivity, resistance, and secondary effects. Annu. Rev. Entomol. 58, 99–117 (2013).

    CAS  PubMed  Google Scholar 

  47. Nieva, J. L., Madan, V. & Carrasco, L. Viroporins: structure and biological functions. Nat. Rev. Microbiol. 10, 563–574 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Hay, M., Thomas, D. W., Craighead, J. L., Economides, C. & Rosenthal, J. Clinical development success rates for investigational drugs. Nat. Biotechnol. 32, 40–51 (2014). This is a very informative review article analysing the development success rates of different drug classes and modalities.

    CAS  PubMed  Google Scholar 

  49. Gilhus, N. E. et al. Myasthenia gravis - autoantibody characteristics and their implications for therapy. Nat. Rev. Neurol. 12, 259–268 (2016).

    CAS  PubMed  Google Scholar 

  50. Titulaer, M. J., Lang, B. & Verschuuren, J. J. Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies. Lancet Neurol. 10, 1098–1107 (2011).

    PubMed  Google Scholar 

  51. Bradl, M., Reindl, M. & Lassmann, H. Mechanisms for lesion localization in neuromyelitis optica spectrum disorders. Curr. Opin. Neurol. 31, 325–333 (2018).

    PubMed  PubMed Central  Google Scholar 

  52. Holz, G. G. & Chepurny, O. G. Glucagon-like peptide-1 synthetic analogs: new therapeutic agents for use in the treatment of diabetes mellitus. Cur. Med. Chem. 10, 2471–2483 (2003).

    CAS  Google Scholar 

  53. Fosgerau, K. & Hoffmann, T. Peptide therapeutics: current status and future directions. Drug Discov. Today 20, 122–128 (2015).

    CAS  PubMed  Google Scholar 

  54. Al Musaimi, O., Al Shaer, D., de la Torre, B. G. & Albericio, F. 2017 FDA peptide harvest. Pharmaceuticals (Basel) 11, E42 (2018).

    Google Scholar 

  55. King, G. F. Venoms as a platform for human drugs: translating toxins into therapeutics. Expert Opin. Biol. Ther. 11, 1469–1484 (2011).

    CAS  PubMed  Google Scholar 

  56. Robinson, S. D., Undheim, E. A. B., Ueberheide, B. & King, G. F. Venom peptides as therapeutics: advances, challenges and the future of venom-peptide discovery. Expert. Rev. Proteom. 14, 931–939 (2017).

    CAS  Google Scholar 

  57. Norton, R. S. & Chandy, K. G. Venom-derived peptide inhibitors of voltage-gated potassium channels. Neuropharmacology 127, 124–138 (2017).

    CAS  PubMed  Google Scholar 

  58. Pennington, M. W., Czerwinski, A. & Norton, R. S. Peptide therapeutics from venom: current status and potential. Bioorg. Med. Chem. 26, 2738–2758 (2018).

    CAS  PubMed  Google Scholar 

  59. Beeton, C., Gutman, G. A. & Chandy, K. G. in The Handbook of Biologically Active Peptides (ed. Kastin, A. J.) 403–413 (Academic Press, 2006).

  60. Narahashi, T., Anderson, N. C. & Moore, J. W. Tetrodotoxin does not block excitation from inside the nerve membrane. Science 153, 765–767 (1966).

    CAS  PubMed  Google Scholar 

  61. McQuarrie, C., Salvaterra, P. M., De Blas, A., Routes, J. & Mahler, H. R. Studies on nicotinic acetylcholine receptors in mammalian brain. Preliminary characterization of membrane-bound alpha-bungarotoxin receptors in rat cerebral cortex. J. Biol. Chem. 251, 6335–6339 (1976).

    CAS  PubMed  Google Scholar 

  62. Ray, R., Morrow, C. S. & Catterall, W. A. Binding of scorpion toxin to receptor sites associated with voltage-sensitive sodium channels in synaptic nerve ending particles. J. Biol. Chem. 253, 7307–7313 (1978).

    CAS  PubMed  Google Scholar 

  63. Safavi-Hemami, H., Brogan, S. E. & Olivera, B. M. Pain therapeutics from cone snail venoms: from Ziconotide to novel non-opioid pathways. J. Proteom. 190, 12–20 (2019). This is an excellent review article describing the development of ziconotide from its discovery to its current role in clinical practice.

    CAS  Google Scholar 

  64. Kerr, L. M. & Yoshikami, D. A venom peptide with a novel presynaptic blocking action. Nature 308, 282–284 (1984).

    CAS  PubMed  Google Scholar 

  65. Olivera, B. M. et al. Peptide neurotoxins from fish-hunting cone snails. Science 230, 1338–1343 (1985).

    CAS  PubMed  Google Scholar 

  66. McCleskey, E. W. et al. Omega-conotoxin: direct and persistent blockade of specific types of calcium channels in neurons but not muscle. Proc. Natl Acad. Sci. USA 84, 4327–4331 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Schmidtko, A., Lotsch, J., Freynhagen, R. & Geisslinger, G. Ziconotide for treatment of severe chronic pain. Lancet 375, 1569–1577 (2010).

    CAS  PubMed  Google Scholar 

  68. Deuis, J. R. et al. Pharmacological characterisation of the highly NaV1.7 selective spider venom peptide Pn3a. Sci. Rep. 7, 40883 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Moyer, B. D. et al. Pharmacological characterization of potent and selective NaV1.7 inhibitors engineered from Chilobrachys jingzhao tarantula venom peptide JzTx-V. PLOS ONE 13, e0196791 (2018).

    PubMed  PubMed Central  Google Scholar 

  70. Minett, M. S. et al. Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel NaV1.7. Nat. Commun. 6, 8967 (2015).

    CAS  PubMed  Google Scholar 

  71. Isensee, J. et al. Synergistic regulation of serotonin and opioid signaling contributes to pain insensitivity in NaV1.7 knockout mice. Sci. Signal. 10, eaah4874 (2017).

    PubMed  PubMed Central  Google Scholar 

  72. Pereira, V. et al. Analgesia linked to NaV1.7 loss of function requires μ- and δ-opioid receptors. Wellcome Open Res. 3, 101 (2018).

    PubMed  PubMed Central  Google Scholar 

  73. Vincler, M. et al. Molecular mechanism for analgesia involving specific antagonism of α9α10 nicotinic acetylcholine receptors. Proc. Natl Acad. Sci. USA 103, 17880–17884 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Clark, R. J., Fischer, H., Nevin, S. T., Adams, D. J. & Craik, D. J. The synthesis, structural characterization, and receptor specificity of the α-conotoxin Vc1.1. J. Biol. Chem. 281, 23254–23263 (2006).

    CAS  PubMed  Google Scholar 

  75. Ellison, M. et al. α-RgIA: a novel conotoxin that specifically and potently blocks the α9α10 nAChR. Biochemistry 45, 1511–1517 (2006).

    CAS  PubMed  Google Scholar 

  76. Callaghan, B. et al. Analgesic α-conotoxins Vc1.1 and Rg1A inhibit N-type calcium channels in rat sensory neurons via GABAB receptor activation. J. Neurosci. 28, 10943–10951 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Castro, J. et al. α-Conotoxin Vc1.1 inhibits human dorsal root ganglion neuroexcitability and mouse colonic nociception via GABAB receptors. Gut 66, 1083–1094 (2017).

    CAS  PubMed  Google Scholar 

  78. Azam, L. & McIntosh, J. M. Molecular basis for the differential sensitivity of rat and human α9α10 nAChRs to α-conotoxin RgIA. J. Neurochem. 122, 1137–1144 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Romero, H. K. et al. Inhibition of α9α10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain. Proc. Natl Acad. Sci. USA 114, E1825–E1832 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Grishin, E. V. et al. Novel peptide from spider venom inhibits P2X3 receptors and inflammatory pain. Ann. Neurol. 67, 680–683 (2010).

    CAS  PubMed  Google Scholar 

  81. DeBin, J. A., Maggio, J. E. & Strichartz, G. R. Purification and characterization of chlorotoxin, a chloride channel ligand from the venom of the scorpion. Am. J. Physiol. 264, C361–C369 (1993).

    CAS  PubMed  Google Scholar 

  82. Ullrich, N., Gillespie, G. Y. & Sontheimer, H. Human astrocytoma cells express a unique chloride current. Neuroreport 7, 343–347 (1995).

    CAS  PubMed  Google Scholar 

  83. Ullrich, N. & Sontheimer, H. Biophysical and pharmacological characterization of chloride currents in human astrocytoma cells. Am. J. Physiol. 270, C1511–C1521 (1996).

    CAS  PubMed  Google Scholar 

  84. Soroceanu, L., Manning, T. J. Jr & Sontheimer, H. Modulation of glioma cell migration and invasion using Cl− and K+ ion channel blockers. J. Neurosci. 19, 5942–5954 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Deshane, J., Garner, C. C. & Sontheimer, H. Chlorotoxin inhibits glioma cell invasion via matrix metalloproteinase-2. J. Biol. Chem. 278, 4135–4144 (2003).

    CAS  PubMed  Google Scholar 

  86. Maertens, C., Wei, L., Tytgat, J., Droogmans, G. & Nilius, B. Chlorotoxin does not inhibit volume-regulated, calcium-activated and cyclic AMP-activated chloride channels. Br. J. Pharmacol. 129, 791–801 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Stroud, M. R., Hansen, S. J. & Olson, J. M. In vivo bio-imaging using chlorotoxin-based conjugates. Curr. Pharm. Des. 17, 4362–4371 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Parrish-Novak, J. et al. Nonclinical profile of BLZ-100, a tumor-targeting fluorescent imaging agent. Int. J. Toxicol. 36, 104–112 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Lehen’kyi, V., Raphael, M. & Prevarskaya, N. The role of the TRPV6 channel in cancer. J. Physiol. 590, 1369–1376 (2012).

    PubMed  PubMed Central  Google Scholar 

  90. Bowen, C. V. et al. In vivo detection of human TRPV6-rich tumors with anti-cancer peptides derived from soricidin. PLOS ONE 8, e58866 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Fu, S. et al. First-in-human phase I study of SOR-C13, a TRPV6 calcium channel inhibitor, in patients with advanced solid tumors. Invest. New Drugs 35, 324–333 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Xiong, Z. G. et al. Neuroprotection in ischemia: blocking calcium-permeable acid-sensing ion channels. Cell 118, 687–698 (2004).

    CAS  PubMed  Google Scholar 

  93. Chassagnon, I. R. et al. Potent neuroprotection after stroke afforded by a double-knot spider-venom peptide that inhibits acid-sensing ion channel 1a. Proc. Natl Acad. Sci. USA 114, 3750–3755 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Richards, K. L. et al. Selective NaV1.1 activation rescues Dravet syndrome mice from seizures and premature death. Proc. Natl Acad. Sci. USA 115, E8077–E8085 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Proctor, C. M. et al. Electrophoretic drug delivery for seizure control. Sci. Adv. 4, eaau1291 (2018).

    PubMed  PubMed Central  Google Scholar 

  96. DeCoursey, T. E., Chandy, K. G., Gupta, S. & Cahalan, M. D. Voltage-gated K+ channels in human T lymphocytes: a role in mitogenesis? Nature 307, 465–468 (1984).

    CAS  PubMed  Google Scholar 

  97. Matteson, D. R. & Deutsch, C. K channels in T lymphocytes: a patch clamp study using monoclonal antibody adhesion. Nature 307, 468–471 (1984).

    CAS  PubMed  Google Scholar 

  98. Cahalan, M. D. & Chandy, K. G. The functional network of ion channels in T lymphocytes. Immunol. Rev. 231, 59–87 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Feske, S., Wulff, H. & Skolnik, E. Y. Ion channels in innate and adaptive immunity. Ann. Rev. Immunol. 33, 291–353 (2015).

    CAS  Google Scholar 

  100. Beeton, C. et al. KV1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases. Proc. Natl Acad. Sci. USA 103, 17414–17419 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Pennington, M. et al. Chemical synthesis and characterization of ShK toxin: a potent potassium channel inhibitor from a sea anemone. Int. J. Pept. Protein Res. 346, 354–358 (1995).

    Google Scholar 

  102. Kalman, K. et al. ShK-Dap22, a potent KV1.3-specific immunosuppressive polypeptide. J. Biol. Chem. 273, 32697–32707 (1998).

    CAS  PubMed  Google Scholar 

  103. Beeton, C. et al. Targeting effector memory T cells with a selective peptide inhibitor of Kv1.3 channels for therapy of autoimmune diseases. Mol. Pharmacol. 67, 1369–1381 (2005).

    CAS  PubMed  Google Scholar 

  104. Tarcha, E. J. et al. Durable pharmacological responses from the peptide drug ShK-186, a specific KV1.3 channel inhibitor that suppresses T cell mediators of autoimmune disease. J. Pharmacol. Exp. Ther. 342, 642–653 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Chi, V. et al. Development of a sea anemone toxin as an immunomodulator for therapy of autoimmune diseases. Toxicon 59, 529–546 (2012).

    CAS  PubMed  Google Scholar 

  106. Tarcha, E. J. et al. Safety and pharmacodynamics of dalazatide, a Kv1.3 channel inhibitor, in the treatment of plaque psoriasis: a randomized phase 1b trial. PLOS ONE 12, e0180762 (2017).

    PubMed  PubMed Central  Google Scholar 

  107. Mozaffar, T., Wencel, M., Goyal, N., Philips, C. & Olsen, C. KV1.3 expression on effector memory T cells in sporadic inclusion body myositis: potential for targeted immunotherapy with dalazatide. Neuromuscul. Disord. 27, S158 (2017).

    Google Scholar 

  108. Tanner, M. R. et al. Prolonged immunomodulation in inflammatory arthritis using the selective Kv1.3 channel blocker HsTX1[R14A] and its PEGylated analog. Clin. Immunol. 180, 45–57 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Zhang, H. K. et al. Autocrine-based selection of drugs that target ion channels from combinatorial venom peptide libraries. Angew. Chem. Int. Ed. Engl. 55, 9306–9310 (2016).

    CAS  PubMed  Google Scholar 

  110. Wang, R. S. E. et al. Rational design of a Kv1.3 channel-blocking antibody as a selective immunosuppressant. Proc. Natl Acad. Sci. USA 113, 11501–11506 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Jin, L. et al. Buccal mucosal delivery of a potent peptide leads to therapeutically-relevant plasma concentrations for the treatment of autoimmune diseases. J. Control. Release 199, 37–44 (2015).

    CAS  PubMed  Google Scholar 

  112. Jin, L. et al. Pulmonary delivery of the KV1.3-blocking peptide HsTX1[R14A] for the treatment of autoimmune diseases. J. Pharm. Sci. 105, 650–656 (2016).

    CAS  PubMed  Google Scholar 

  113. Murray, J. K. et al. Pharmaceutical optimization of peptide toxins for ion channel targets: potent, selective, and long-lived antagonists of KV1.3. J. Med. Chem. 58, 6784–6802 (2015).

    CAS  PubMed  Google Scholar 

  114. Edwards, W. et al. Targeting the ion channel KV1.3 with scorpion venom peptides engineered for potency, selectivity, and half-life. J. Biol. Chem. 289, 22704–22714 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Fung-Leung, W. P. et al. T cell subset and stimulation strength-dependent modulation of T cell activation by KV1.3 blockers. PLOS ONE 12, e0170102 (2017).

    PubMed  PubMed Central  Google Scholar 

  116. Chiang, E. Y. et al. Potassium channels KV1.3 and KCa3.1 cooperatively and compensatorily regulate antigen-specific memory T cell functions. Nat. Commun. 8, 14644 (2017).

    PubMed  PubMed Central  Google Scholar 

  117. Markgraf, R. et al. Mechanism and molecular basis for the sodium channel subtype specificity of micro-conopeptide CnIIIC. Br. J. Pharmacol. 167, 576–586 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Del Rio-Sancho, S., Cros, C., Coutaz, B., Cuendet, M. & Kalia, Y. N. Cutaneous iontophoresis of μ-conotoxin CnIIIC. A potent NaV1.4 antagonist with analgesic, anaesthetic and myorelaxant properties. Int. J. Pharm. 518, 59–65 (2017).

    PubMed  Google Scholar 

  119. Balaev, A. N., Okhmanovich, K. A. & Osipov, V. N. A shortened, protecting group free, synthesis of the anti-wrinkle venom analogue Syn-Ake (R) exploiting an optimized Hofmann-type rearrangement. Tetrahedron Lett. 55, 5745–5747 (2014).

    CAS  Google Scholar 

  120. Goliger, J. A. & Paul, D. L. Wounding alters epidermal connexin expression and gap junction-mediated intercellular communication. Mol. Biol. Cell 6, 1491–1501 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Grek, C. L. et al. Topical administration of a connexin43-based peptide augments healing of chronic neuropathic diabetic foot ulcers: a multicenter, randomized trial. Wound Repair Regen. 23, 203–212 (2015).

    PubMed  PubMed Central  Google Scholar 

  122. Ghatnekar, G. S., Grek, C. L., Armstrong, D. G., Desai, S. C. & Gourdie, R. G. The effect of a connexin43-based peptide on the healing of chronic venous leg ulcers: a multicenter, randomized trial. J. Invest. Dermatol. 135, 289–298 (2015). This publication describes a clinical trial demonstrating that the connexin 43-targeted peptide ACT1 improves healing of leg ulcers.

    CAS  PubMed  Google Scholar 

  123. Strohl, W. R. Fusion proteins for half-life extension of biologics as a strategy to make biobetters. BioDrugs 29, 215–239 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Chandy, K. G. & Norton, R. S. Peptide blockers of KV1.3 channels in T cells as therapeutics for autoimmune disease. Curr. Opin. Chem. Biol. 38, 97–107 (2017).

    CAS  PubMed  Google Scholar 

  125. Kaspar, A. A. & Reichert, J. M. Future directions for peptide therapeutics development. Drug Discov. Today 18, 807–817 (2013).

    CAS  PubMed  Google Scholar 

  126. Bhardwaj, G. et al. Accurate de novo design of hyperstable constrained peptides. Nature 538, 329–335 (2016). This study describes the development of computational methods for accurate de novo design of conformationally restricted peptides and the use of these methods to design 18–47-residue, disulfide-crosslinked peptides, a subset of which are heterochiral and/or N–C backbone cyclized.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Halai, R. et al. Effects of cyclization on stability, structure, and activity of α-conotoxin RgIA at the α9α10 nicotinic acetylcholine receptor and GABAB receptor. J. Med. Chem. 54, 6984–6992 (2011).

    CAS  PubMed  Google Scholar 

  128. Kwon, S. et al. Efficient enzymatic cyclization of an inhibitory cystine knot-containing peptide. Biotechnol. Bioeng. 113, 2202–2212 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Bergeron, Z. L. & Bingham, J. P. Scorpion toxins specific for potassium (K+) channels: a historical overview of peptide bioengineering. Toxins (Basel) 4, (1082–1119 (2012).

    Google Scholar 

  130. Clark, R. J. et al. Engineering stable peptide toxins by means of backbone cyclization: stabilization of the α-conotoxin MII. Proc. Natl Acad. Sci. USA 102, 13767–13772 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Jensen, J. E. et al. Cyclisation increases the stability of the sea anemone peptide APETx2 but decreases its activity at acid-sensing ion channel 3. Mar. Drugs 10, 1511–1527 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. van Lierop, B. J. et al. Dicarba α-conotoxin Vc1.1 analogues with differential selectivity for nicotinic acetylcholine and GABAB receptors. ACS Chem. Biol. 8, 1815–1821 (2013).

    PubMed  Google Scholar 

  133. Yu, R. et al. Less is more: design of a highly stable disulfide-deleted mutant of analgesic cyclic α-conotoxin Vc1.1. Sci. Rep. 5, 13264 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Platt, R. J. et al. Stapling mimics noncovalent interactions of γ-carboxyglutamates in conantokins, peptidic antagonists of N-methyl-D-aspartic acid receptors. J. Biol. Chem. 287, 20727–20736 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Harvey, A. J., Gable, R. W. & Baell, J. B. A three-residue, continuous binding epitope peptidomimetic of ShK toxin as a KV1.3 inhibitor. Bioorg. Med. Chem. Lett. 15, 3193–3196 (2005).

    CAS  PubMed  Google Scholar 

  136. Chen, R. et al. Peptidomimetic star polymers for targeting biological ion channels. PLOS ONE 11, e0152169 (2016).

    PubMed  PubMed Central  Google Scholar 

  137. Tranberg, C. E. et al. ω-Conotoxin GVIA mimetics that bind and inhibit neuronal CaV2.2 ion channels. Mar. Drugs 10, 2349–2368 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Mollica, A. et al. Design, synthesis and biological evaluation of two opioid agonist and CaV2.2 blocker multitarget ligands. Chem. Biol. Drug Des. 86, 156–162 (2015).

    CAS  PubMed  Google Scholar 

  139. Rusconi, F. et al. Peptidomimetic targeting of CaVβ2 overcomes dysregulation of the L-type calcium channel density and recovers cardiac function. Circulation 134, 534–546 (2016).

    CAS  PubMed  Google Scholar 

  140. Michne, W. et al. Novel inhibitors of potassium ion channels on human T lymphocytes. J. Med. Chem. 38, 1877–1883 (1995).

    CAS  PubMed  Google Scholar 

  141. Hill, R. J. et al. WIN 17317-3: novel nonpeptide antagonist of voltage-activated K+ channels in human T lymphocytes. Mol. Pharmacol. 48, 98–104 (1995).

    CAS  PubMed  Google Scholar 

  142. Nguyen, A. et al. Novel nonpeptide agents potently block the C-type inactivated conformation of Kv1.3 and suppress T cell activation. Mol. Pharmacol. 50, 1672–1679 (1996).

    CAS  PubMed  Google Scholar 

  143. Knaus, H. G. et al. Tremorgenic indole alkaloids potently inhibit smooth muscle high- conductance calcium-activated potassium channels. Biochemistry 33, 5819–5828 (1994).

    CAS  PubMed  Google Scholar 

  144. Carter, P. J. & Lazar, G. A. Next generation antibody drugs: pursuit of the ‘high-hanging fruit’. Nat. Rev. Drug Discov. 17, 197–223 (2018). This is a very informative and comprehensive review about the current stage of antibody drug development.

    CAS  PubMed  Google Scholar 

  145. Gilbert, S. M. et al. A phase I clinical trial demonstrates that nfP2X7 -targeted antibodies provide a novel, safe and tolerable topical therapy for basal cell carcinoma. Br. J. Dermatol. 177, 117–124 (2017). This publication describes the phase I clinical trial for a P2X7-targeted antibody therapeutic.

    CAS  PubMed  Google Scholar 

  146. Kamath, A. V. Translational pharmacokinetics and pharmacodynamics of monoclonal antibodies. Drug Discov. Today Technol. 21–22, 75–83 (2016).

    PubMed  Google Scholar 

  147. Shcherbatko, A. et al. Modulation of P2X3 and P2X2/3 receptors by monoclonal antibodies. J. Biol. Chem. 291, 12254–12270 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Vernino, S. Autoimmune and paraneoplastic channelopathies. Neurotherapeutics 4, 305–314 (2007).

    CAS  PubMed  Google Scholar 

  149. Sun, H. & Li, M. Antibody therapeutics targeting ion channels: are we there yet? Acta Pharmacol. Sin. 34, 199–204 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Gomez-Varela, D. et al. Monoclonal antibody blockade of the human Eag1 potassium channel function exerts antitumor activity. Cancer Res. 67, 7343–7349 (2007).

    CAS  PubMed  Google Scholar 

  151. Lin, F. F. et al. Generation and characterization of fully human monoclonal antibodies against human Orai1 for autoimmune disease. J. Pharmacol. Exp. Ther. 345, 225–238 (2013).

    CAS  PubMed  Google Scholar 

  152. Cox, J. H. et al. Antibody-mediated targeting of the Orai1 calcium channel inhibits T cell function. PLOS ONE 8, e82944 (2013).

    PubMed  PubMed Central  Google Scholar 

  153. Sun, H. et al. A monoclonal antibody against KCNK9 K+ channel extracellular domain inhibits tumour growth and metastasis. Nat. Commun. 7, 10339 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. MacDonald, L., Gao, M., Morra, M., Alessandri-Haber, N. M. & LaCroix-Fralish, M. L. Anti-ASIC1 antibodies and uses thereof. US patent US9371383 (2016).

  155. Stortelers, C., Pinto-Espinoza, C., Van Hoorick, D. & Koch-Nolte, F. Modulating ion channel function with antibodies and nanobodies. Curr. Opin. Immunol. 52, 18–26 (2018).

    CAS  PubMed  Google Scholar 

  156. Buell, G. et al. Blockade of human P2X7 receptor function with a monoclonal antibody. Blood 92, 3521–3528 (1998).

    CAS  PubMed  Google Scholar 

  157. Mettler Izquierdo, S. et al. High-efficiency antibody discovery achieved with multiplexed microscopy. Microscopy (Oxf.) 65, 341–352 (2016).

    Google Scholar 

  158. Bednenko, J. et al. A multiplatform strategy for the discovery of conventional monoclonal antibodies that inhibit the voltage-gated potassium channel KV1.3. MAbs 10, 636–650 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Qiang, M. et al. Selection of an ASIC1a-blocking combinatorial antibody that protects cells from ischemic death. Proc. Natl Acad. Sci. USA 115, E7469–E7477 (2018). This study describes the generation of a functional ASIC1a-blocking antibody using expression in nanodiscs to achieve a conformation as close as possible to the natural state of the channel in the plasma membrane.

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Hamers-Casterman, C. et al. Naturally occurring antibodies devoid of light chains. Nature 363, 446–448 (1993).

    CAS  PubMed  Google Scholar 

  161. Muyldermans, S. Nanobodies: natural single-domain antibodies. Annu. Rev. Biochem. 82, 775–797 (2013).

    CAS  PubMed  Google Scholar 

  162. Ingram, J. R., Schmidt, F. I. & Ploegh, H. L. Exploiting nanobodies’ singular traits. Ann. Rev. Immunol. 36, 695–715 (2018).

    CAS  Google Scholar 

  163. Vazquez-Lombardi, R. et al. Challenges and opportunities for non-antibody scaffold drugs. Drug Discov. Today 20, 1271–1283 (2015).

    CAS  PubMed  Google Scholar 

  164. Stockbridge, R. B., Koide, A., Miller, C. & Koide, S. Proof of dual-topology architecture of Fluc F− channels with monobody blockers. Nat. Commun. 5, 5120 (2014).

    CAS  PubMed  Google Scholar 

  165. Sennhauser, G., Amstutz, P., Briand, C., Storchenegger, O. & Grutter, M. G. Drug export pathway of multidrug exporter AcrB revealed by DARPin inhibitors. PLOS Biol. 5, e7 (2007).

    PubMed  Google Scholar 

  166. Gilbert, S. M. et al. ATP in the tumour microenvironment drives expression of nfP2X7, a key mediator of cancer cell survival. Oncogene https://doi.org/10.1038/s41388-018-0426-6 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  167. Danquah, W. et al. Nanobodies that block gating of the P2X7 ion channel ameliorate inflammation. Sci. Transl Med. 8, 366ra162 (2016). This study describes the generation and characterization of P2X7-blocking nanobodies and demonstrates their efficacy in proof-of-concept animal models.

    PubMed  Google Scholar 

  168. Matheu, M. P. et al. Imaging of effector memory T cells during a delayed-type hypersensitivity reaction and suppression by KV1.3 channel block. Immunity 29, 602–614 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Yang, X. F. et al. The antibody targeting the E314 peptide of human KV1.3 pore region serves as a novel, potent and specific channel blocker. PLOS ONE 7, e36379 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Fan, C. et al. A novel PADRE-KV1.3 vaccine effectively induces therapeutic antibodies and ameliorates experimental autoimmune encephalomyelitis in rats. Clin. Immunol. 193, 98–109 (2018).

    CAS  PubMed  Google Scholar 

  171. Vellatt, A. K. KnotBodiesTM: creating ion channel blocking antibodies by fusing Knottins into peripheral CDR loops. Presented at the Precision Medicine and Ion Channel Retreat 2017

  172. Lee, J. H. et al. A monoclonal antibody that targets a NaV1.7 channel voltage sensor for pain and itch relief. Cell 157, 1393–1404 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Dong, L. et al. Evaluation of recombinant monoclonal antibody SVmab1 binding to NaV1.7 target sequences and block of human NaV1.7 currents. F1000Res 5, 2764 (2016).

    Google Scholar 

  174. Bang, S. et al. Differential inhibition of NaV1.7 and neuropathic pain by hybridoma-produced and recombinant monoclonal antibodies that target NaV1.7: differential activities of NaV1.7-targeting monoclonal antibodies. Neurosci. Bull. 34, 22–41 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Biswas, K. et al. Engineering antibody reactivity for efficient derivatization to generate NaV1.7 inhibitory GpTx-1 peptide-antibody conjugates. ACS Chem. Biol. 12, 2427–2435 (2017).

    CAS  PubMed  Google Scholar 

  176. Douthwaite, J. A., Finch, D. K., Mustelin, T. & Wilkinson, T. C. Development of therapeutic antibodies to G protein-coupled receptors and ion channels: opportunities, challenges and their therapeutic potential in respiratory diseases. Pharmacol. Ther. 169, 113–123 (2017).

    CAS  PubMed  Google Scholar 

  177. Ayoub, M. A. et al. Antibodies targeting G protein-coupled receptors: recent advances and therapeutic challenges. MAbs 9, 735–741 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Magnani, F. et al. A mutagenesis and screening strategy to generate optimally thermostabilized membrane proteins for structural studies. Nat. Protoc. 11, 1554–1571 (2016).

    PubMed  PubMed Central  Google Scholar 

  179. Serrano-Vega, M. J., Magnani, F., Shibata, Y. & Tate, C. G. Conformational thermostabilization of the β1-adrenergic receptor in a detergent-resistant form. Proc. Natl Acad. Sci. USA 105, 877–882 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Starkie, D. O., Compson, J. E., Rapecki, S. & Lightwood, D. J. Generation of recombinant monoclonal antibodies from immunised mice and rabbits via flow cytometry and sorting of antigen-specific IgG+ memory B cells. PLOS ONE 11, e0152282 (2016).

    PubMed  PubMed Central  Google Scholar 

  181. Rouet, R., Jackson, K. J. L., Langley, D. B. & Christ, D. Next-generation sequencing of antibody display repertoires. Front. Immunol. 9, 118 (2018).

    PubMed  PubMed Central  Google Scholar 

  182. Yang, W. et al. Next-generation sequencing enables the discovery of more diverse positive clones from a phage-displayed antibody library. Exp. Mol. Med. 49, e308 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Earl, L. A., Falconieri, V., Milne, J. L. & Subramaniam, S. Cryo-EM: beyond the microscope. Curr. Opin. Struct. Biol. 46, 71–78 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Wang, R. Y. et al. Automated structure refinement of macromolecular assemblies from cryo-EM maps using Rosetta. eLife 5, e17219 (2016).

    PubMed  PubMed Central  Google Scholar 

  185. Shen, H. et al. Structural basis for the modulation of voltage-gated sodium channels by animal toxins. Science 362, 6412 (2018).

    Google Scholar 

  186. Gonzalez-Sapienza, G. & Rossotti, M. A. & Tabares-da Rosa, S. Single-domain antibodies as versatile affinity reagents for analytical and diagnostic applications. Front. Immunol. 8, 977 (2017).

    PubMed  PubMed Central  Google Scholar 

  187. Vincke, C. & Muyldermans, S. in Single Domain Antibodies (eds Saerens, D. & Muyldermans, S.) Vol. 911 15–26 (Humana Press, 2012).

  188. Sela-Culang, I., Kunik, V. & Ofran, Y. The structural basis of antibody-antigen recognition. Front. Immunol. 4, 302 (2013).

    PubMed  PubMed Central  Google Scholar 

  189. Inoue, A., Sawata, S. Y., Taira, K. & Wadhwa, R. Loss-of-function screening by randomized intracellular antibodies: identification of hnRNP-K as a potential target for metastasis. Proc. Natl Acad. Sci. USA 104, 8983–8988 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Schmidt, F. I. et al. Phenotypic lentivirus screens to identify functional single domain antibodies. Nat. Microbiol. 1, 16080 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Caussinus, E., Kanca, O. & Affolter, M. Fluorescent fusion protein knockout mediated by anti-GFP nanobody. Nat. Struct. Mol. Biol. 19, 117–121 (2011).

    PubMed  Google Scholar 

  192. Kuo, C.-L., Oyler, G. A. & Shoemaker, C. B. Accelerated neuronal cell recovery from Botulinum neurotoxin intoxication by targeted ubiquitination. PLOS ONE 6, e20352 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Rasmussen, S. G. F. et al. Structure of a nanobody-stabilized active state of the β2- adrenoceptor. Nature 469, 175–180 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Kruse, A. C. et al. Activation and allosteric modulation of a muscarinic acetylcholine receptor. Nature 504, 101–106 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Heijman, J. & Dobrev, D. Ion channels as part of macromolecular multiprotein complexes: clinical significance. Herzschrittmacherther Elektrophysiol 29, 30–35 (2018).

    PubMed  Google Scholar 

  196. Long, S. B., Tao, X., Campbell, E. B. & MacKinnon, R. Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment. Nature 450, 376–382 (2007). This study describes the X-ray structure of a K V in a lipid environment and has been very helpful for explaining voltage sensor movement and gating.

    CAS  PubMed  Google Scholar 

  197. Shen, H. et al. Structure of a eukaryotic voltage-gated sodium channel at near-atomic resolution. Science 355, eaal4326 (2017).

    PubMed  Google Scholar 

  198. Hutchings, C. J., Colussi, P. & Clark, T. G. Ion channels as therapeutic antibody targets. MAbs 10, 1–32 (2018).

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Acknowledgements

The authors thank A. Karatt Vellatt at IONTAS for providing the Protein Data Bank (PDB) file of the X-ray coordinates of a KnotBody antigen-binding fragment (Fab) for figure 3. The authors are supported by the CounterACT Program, US National Institutes of Health Office of the Director (NIH OD) and the US National Institute of Neurological Disorders and Stroke (NINDS) (grant numbers U54NS079202 and NS100294 to H.W.); and the Singapore Ministry of Health’s National Ministry Research Council under its Clinician–Scientist Individual Research Grant (NMRC/CIRG/1427/2015) and the Singapore Ministry of Education Academic Research Fund Tier 1 (2015-T1-022-047) and Tier 2 (MOE2016-T2-2-032) (to K.G.C).

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Authors and Affiliations

  1. Department of Pharmacology, University of California Davis, Davis, CA, USA

    Heike Wulff

  2. Saniona A/S, Ballerup, Denmark

    Palle Christophersen

  3. TetraGenetics Inc., Arlington, MA, USA

    Paul Colussi

  4. Molecular Physiology Laboratory, Infection and Immunity Theme, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore

    K. George Chandy

  5. Department of Physiology & Membrane Biology, University of California Davis, Davis, CA, USA

    Vladimir Yarov-Yarovoy

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Supplementary information

Glossary

Patch-clamp technology

Patch-clamp is an electrophysiological technique in which a glass pipette is sealed tightly to the cell membrane of an individual cell. In the most common voltage-clamp configurations, voltage across the cell membrane is controlled by the experimenter, and the resulting currents are recorded. Patch-clamp is considered the gold-standard in the ion channel field and has been automated for higher throughput.

Giga seal electrophysiological recordings

Electrophysiological recordings in which a glass pipette is sealed so tightly to the membrane of a cell that it creates a giga seal, meaning a >109 Ohm leak resistance. This causes low noise and excellent mechanical stability, which allows recording of single ion channels in patches of membranes as well as of all channels in a cell.

Bouton

A synaptic bouton is a button-like swelling on the terminal ends of axons. Synaptic boutons are typically the sites where synapses with other neurons are found and where neurotransmitters are stored and released to communicate with other neurons via these synapses.

Postictal

The state or period after a seizure (time from the ending of an epileptic event until full mental recovery is achieved).

Antibody-dependent cellular cytotoxicity

A process in which an effector cell of the immune system (such as a natural killer cell, a macrophage, a neutrophil or an eosinophil) actively lyses a cell whose membrane surface antigens have been bound by antibodies. The crystallizable fragment (Fc) portion of the antibody allows the immune cell to bind the antibody.

Complement-dependent cytotoxicity

The killing of an antibody-coated target cell via recruitment of the complement system (a set of circulating plasma proteins).

Antibody-dependent cellular phagocytosis

The engulfment of an antibody-coated cell by phagocytes such as macrophages, neutrophils or dendritic cells.

FcRn-mediated transcytosis

The neonatal crystallizable fragment (Fc) receptor (FcRn) is an Fc receptor that is capable of transporting immunoglobulin G (IgG) from mother’s milk across the epithelium of the gastrointestinal tract or across the placenta to the fetus. Binding to FcRn can be used to try and transport antibodies across epithelia.

Epitope binning analysis

An epitope or antigenic determinant is the part of the antigen that is recognized by an antibody. Epitope binning analysis refers to the process of first characterizing and then sorting a library of monoclonal antibodies into groups binding to the same or closely related epitopes on the basis of their ability to block each other’s binding.

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Wulff, H., Christophersen, P., Colussi, P. et al. Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov 18, 339–357 (2019). https://doi.org/10.1038/s41573-019-0013-8

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