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Protein & Peptide Letters

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ISSN (Print): 0929-8665
ISSN (Online): 1875-5305

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Review Article

Pharmacological Classes of Conus Peptides Targeted to Calcium, Sodium, and Potassium Channels

Author(s): Elsie C. Jimenez*

Volume 30, Issue 11, 2023

Published on: 24 November, 2023

Page: [913 - 929] Pages: 17

DOI: 10.2174/0109298665279447231106072246

Price: $65

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Abstract

This review describes the specific features of families of Conus venom peptides (conotoxins or conopeptides) that represent twelve pharmacological classes. Members of these conopeptide families are targeted to voltage-gated ion channels, such as calcium, sodium, and potassium channels. The conopeptides covered in this work include omega-conotoxins and contryphans with calcium channels as targets; mu-conotoxins, muO-conotoxins, muP-conotoxins, delta-conotoxins and iota-conotoxin with sodium channels as targets; and kappa-conotoxins, kappaM-conotoxins, kappaO-conotoxin, conkunitzins, and conorfamide with potassium channels as targets. The review covers the peptides that have been characterized over the last two decades with respect to their physiological targets and/or potential pharmacological applications, or those that have been discovered earlier but with noteworthy features elucidated in more recent studies. Some of these peptides have the potential to be developed as therapies for nerve, muscle, and heart conditions associated with dysfunctions in voltage-gated ion channels. The gating process of an ion channel subtype in neurons triggers various biological activities, including regulation of gene expression, contraction, neurotransmitter secretion, and transmission of electrical impulses. Studies on conopeptides and their interactions with calcium, sodium, and potassium channels provide evidence for Conus peptides as neuroscience research probes and therapeutic leads.

Keywords: Conotoxin, conopeptide, Conus peptide pharmacological classes, N-type calcium channel, Cav2.2, sodium channels Nav1.1-Nav1.9, Shaker potassium channel, Kv1-Kv12 potassium channels, conopeptide-based therapeutic agent, neuropathic pain therapy.

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[1]
Hu, H.; Bandyopadhyay, P.K.; Olivera, B.M.; Yandell, M. Elucidation of the molecular envenomation strategy of the cone snail Conus geographus through transcriptome sequencing of its venom duct. BMC Genomics, 2012, 13(1), 284.
[http://dx.doi.org/10.1186/1471-2164-13-284] [PMID: 22742208]
[2]
Dutertre, S.; Griffin, J.; Lewis, R.J. Phyla molluska: The venom apparatus of cone snails. In: Marine and freshwater toxins; Gopalakrishnakone, P.; Haddad, V., Jr; Kem, W.; Tubaro, A.; Kim, E., Eds.; Springer: Dordrecht, 2015; pp. 1-10.
[http://dx.doi.org/10.1007/978-94-007-6650-1_8-1]
[3]
Olivera, B.M.; Seger, J.; Horvath, M.P.; Fedosov, A.E. Prey-capture strategies of fish-hunting cone snails: behavior, neurobiology, and evolution. Brain Behav. Evol., 2015, 86(1), 58-74.
[http://dx.doi.org/10.1159/000438449] [PMID: 26397110]
[4]
Gao, B.; Peng, C.; Yang, J.; Yi, Y.; Zhang, J.; Shi, Q. Cone snails: A big store of conotoxins for novel drug discovery. Toxins, 2017, 9(12), 397.
[http://dx.doi.org/10.3390/toxins9120397] [PMID: 29215605]
[5]
Himaya, S.; Lewis, R. Venomics-accelerated cone snail venom peptide discovery. Int. J. Mol. Sci., 2018, 19(3), 788.
[http://dx.doi.org/10.3390/ijms19030788] [PMID: 29522462]
[6]
Jin, A.H.; Muttenthaler, M.; Dutertre, S.; Himaya, S.W.A.; Kaas, Q.; Craik, D.J.; Lewis, R.J.; Alewood, P.F. Conotoxins: Chemistry and biology. Chem. Rev., 2019, 119(21), 11510-11549.
[http://dx.doi.org/10.1021/acs.chemrev.9b00207] [PMID: 31633928]
[7]
Morales Duque, H.; Campos Dias, S.; Franco, O. Structural and functional analyses of cone snail toxins. Mar. Drugs, 2019, 17(6), 370.
[http://dx.doi.org/10.3390/md17060370] [PMID: 31234371]
[8]
Bjørn-Yoshimoto, W.E.; Ramiro, I.B.L.; Yandell, M.; McIntosh, J.M.; Olivera, B.M.; Ellgaard, L.; Safavi-Hemami, H. Curses or cures: A review of the numerous benefits versus the biosecurity concerns of conotoxin research. Biomedicines, 2020, 8(8), 235.
[http://dx.doi.org/10.3390/biomedicines8080235] [PMID: 32708023]
[9]
Jimenez, E.C. Post-translationally modified conopeptides: Biological activities and pharmacological applications. Peptides, 2021, 139, 170525.
[http://dx.doi.org/10.1016/j.peptides.2021.170525] [PMID: 33684482]
[10]
Börjesson, S.I.; Elinder, F. Structure, function, and modification of the voltage sensor in voltage-gated ion channels. Cell Biochem. Biophys., 2008, 52(3), 149-174.
[http://dx.doi.org/10.1007/s12013-008-9032-5] [PMID: 18989792]
[11]
Miceli, F.; Soldovieri, M.V.; Ambrosino, P.; De Maria, M.; Manocchio, L.; Medoro, A.; Taglialatela, M. Molecular pathophysiology and pharmacology of the voltage-sensing module of neuronal ion channels. Front. Cell. Neurosci., 2015, 9, 259.
[http://dx.doi.org/10.3389/fncel.2015.00259] [PMID: 26236192]
[12]
Tosti, E.; Boni, R.; Gallo, A. Pathophysiological responses to conotoxin modulation of voltage-gated ion currents. Mar. Drugs, 2022, 20(5), 282.
[http://dx.doi.org/10.3390/md20050282] [PMID: 35621933]
[13]
Catterall, W.A. Voltage-gated calcium channels. Cold Spring Harb. Perspect. Biol., 2011, 3(8), a003947.
[http://dx.doi.org/10.1101/cshperspect.a003947] [PMID: 21746798]
[14]
Bagal, S.K.; Marron, B.E.; Owen, R.M.; Storer, R.I.; Swain, N.A. Voltage gated sodium channels as drug discovery targets. Channels, 2015, 9(6), 360-366.
[http://dx.doi.org/10.1080/19336950.2015.1079674] [PMID: 26646477]
[15]
Johnston, J.; Forsythe, I.D.; Kopp-Scheinpflug, C. Symposium review: Going native: Voltage-gated potassium channels controlling neuronal excitability. J. Physiol., 2010, 588(17), 3187-3200.
[http://dx.doi.org/10.1113/jphysiol.2010.191973] [PMID: 20519310]
[16]
Yuan, P.; Leonetti, M.D.; Pico, A.R.; Hsiung, Y.; MacKinnon, R. Structure of the human BK channel Ca2+-activation apparatus at 3.0 A resolution. Science, 2010, 329(5988), 182-186.
[http://dx.doi.org/10.1126/science.1190414] [PMID: 20508092]
[17]
Karbat, I.; Altman-Gueta, H.; Fine, S.; Szanto, T.; Hamer-Rogotner, S.; Dym, O.; Frolow, F.; Gordon, D.; Panyi, G.; Gurevitz, M.; Reuveny, E. Pore-modulating toxins exploit inherent slow inactivation to block K + channels. Proc. Natl. Acad. Sci., 2019, 116(37), 18700-18709.
[http://dx.doi.org/10.1073/pnas.1908903116] [PMID: 31444298]
[18]
Olivera, B.M.; McIntosh, J.M.; Curz, L.J.; Luque, F.A.; Gray, W.R. Purification and sequence of a presynaptic peptide toxin from Conus geographus venom. Biochemistry, 1984, 23(22), 5087-5090.
[http://dx.doi.org/10.1021/bi00317a001] [PMID: 6509012]
[19]
Kerr, L.M.; Yoshikami, D. A venom peptide with a novel presynaptic blocking action. Nature, 1984, 308(5956), 282-284.
[http://dx.doi.org/10.1038/308282a0] [PMID: 6608056]
[20]
Feng, Z.P.; Hamid, J.; Doering, C.; Bosey, G.M.; Snutch, T.P.; Zamponi, G.W. Residue Gly1326 of the N-type calcium channel alpha 1B subunit controls reversibility of omega-conotoxin GVIA and MVIIA block. J. Biol. Chem., 2001, 276(19), 15728-15735.
[http://dx.doi.org/10.1074/jbc.M100406200] [PMID: 11279062]
[21]
Gadjanski, I.; Boretius, S.; Williams, S.K.; Lingor, P.; Knöferle, J.; Sättler, M.B.; Fairless, R.; Hochmeister, S.; Sühs, K.W.; Michaelis, T.; Frahm, J.; Storch, M.K.; Bähr, M.; Diem, R. Role of n-type voltage-dependent calcium channels in autoimmune optic neuritis. Ann. Neurol., 2009, 66(1), 81-93.
[http://dx.doi.org/10.1002/ana.21668] [PMID: 19670438]
[22]
Pieri, M.; Caioli, S.; Canu, N.; Mercuri, N.B.; Guatteo, E.; Zona, C. Over-expression of N-type calcium channels in cortical neurons from a mouse model of amyotrophic lateral sclerosis. Exp. Neurol., 2013, 247, 349-358.
[http://dx.doi.org/10.1016/j.expneurol.2012.11.002] [PMID: 23142186]
[23]
Hasan, M.M.; Starobova, H.; Mueller, A.; Vetter, I.; Lewis, R.J. Subcutaneous ω-conotoxins alleviate mechanical pain in rodent models of acute peripheral neuropathy. Mar. Drugs, 2021, 19(2), 106.
[http://dx.doi.org/10.3390/md19020106] [PMID: 33670311]
[24]
Olivera, B.M.; Cruz, L.J.; De Santos, V.; LeCheminant, G.; Griffin, D.; Zeikus, R.; McIntosh, J.M.; Galyean, R.; Varga, J.; Gray, W.R. Neuronal calcium channel antagonists. Discrimination between calcium channel subtypes using. omega.-conotoxin from Conus magus venom. Biochemistry, 1987, 26(8), 2086-2090.
[http://dx.doi.org/10.1021/bi00382a004] [PMID: 2441741]
[25]
Miljanich, G.P. Ziconotide: Neuronal calcium channel blocker for treating severe chronic pain. Curr. Med. Chem., 2004, 11(23), 3029-3040.
[http://dx.doi.org/10.2174/0929867043363884] [PMID: 15578997]
[26]
Rauck, R.L.; Wallace, M.S.; Burton, A.W.; Kapural, L.; North, J.M. Intrathecal ziconotide for neuropathic pain: A review. Pain Pract., 2009, 9(5), 327-337.
[http://dx.doi.org/10.1111/j.1533-2500.2009.00303.x] [PMID: 19682321]
[27]
Schmidtko, A.; Lötsch, J.; Freynhagen, R.; Geisslinger, G. Ziconotide for treatment of severe chronic pain. Lancet, 2010, 375(9725), 1569-1577.
[http://dx.doi.org/10.1016/S0140-6736(10)60354-6] [PMID: 20413151]
[28]
Greenberg, E.N. Ziconitide. J. Pain Palliat. Care Pharmacother., 2011, 25(4), 380-381.
[http://dx.doi.org/10.3109/15360288.2011.625468] [PMID: 22126177]
[29]
Yu, S.; Li, Y.; Chen, J.; Zhang, Y.; Tao, X.; Dai, Q.; Wang, Y.; Li, S.; Dong, M. TAT-modified ω-conotoxin MVIIA for crossing the blood-brain barrier. Mar. Drugs, 2019, 17(5), 286.
[http://dx.doi.org/10.3390/md17050286] [PMID: 31083641]
[30]
Song, K.; Hao, Y.; Tan, X.; Huang, H.; Wang, L.; Zheng, W. Microneedle-mediated delivery of Ziconotide-loaded liposomes fused with exosomes for analgesia. J. Control. Release, 2023, 356, 448-462.
[http://dx.doi.org/10.1016/j.jconrel.2023.03.007] [PMID: 36898532]
[31]
Ding, X.; Wang, Y.; Zhang, S.; Zhang, R.; Chen, D.; Chen, L.; Zhang, Y.; Luo, S.Z.; Xu, J.; Pei, C. Self-assembly nanostructure of myristoylated ω-conotoxin MVIIA increases the duration of efficacy and reduces side effects. Mar. Drugs, 2023, 21(4), 229.
[http://dx.doi.org/10.3390/md21040229] [PMID: 37103368]
[32]
Hillyard, D.R.; Monje, V.D.; Mintz, I.M.; Bean, B.P.; Nadasdi, L.; Ramachandran, J.; Miljanich, G.; Azimi-Zoonooz, A.; McIntosh, J.M.; Cruz, L.J.; Imperial, J.S.; Olivera, B.M. A new conus peptide ligand for mammalian presynaptic Ca2+ channels. Neuron, 1992, 9(1), 69-77.
[http://dx.doi.org/10.1016/0896-6273(92)90221-X] [PMID: 1352986]
[33]
Grantham, C.J.; Bowman, D.; Bath, C.P.; Bell, D.C.; Bleakman, D. ω-conotoxin MVIIC reversibly inhibits a human N-type calcium channel and calcium influx into chick synaptosomes. Neuropharmacology, 1994, 33(2), 255-258.
[http://dx.doi.org/10.1016/0028-3908(94)90017-5] [PMID: 8035912]
[34]
Oliveira, K.M.; Lavor, M.S.; Silva, C.M.; Fukushima, F.B.; Rosado, I.R.; Silva, J.F.; Martins, B.C.; Guimarães, L.B.; Gomez, M.V.; Melo, M.M.; Melo, E.G. Omega-conotoxin MVIIC attenuates neuronal apoptosis in vitro and improves significant recovery after spinal cord injury in vivo in rats. Int. J. Clin. Exp. Pathol., 2014, 7(7), 3524-3536.
[PMID: 25120731]
[35]
Wen, L.; Yang, S.; Qiao, H.; Liu, Z.; Zhou, W.; Zhang, Y.; Huang, P. SO-3, a new O-superfamily conopeptide derived from Conus striatus, selectively inhibits N-type calcium currents in cultured hippocampal neurons. Br. J. Pharmacol., 2005, 145(6), 728-739.
[http://dx.doi.org/10.1038/sj.bjp.0706223] [PMID: 15880145]
[36]
Dai, Q.; Liu, F.; Zhou, Y.; Lu, B.; Yu, F.; Huang, P. The synthesis of SO-3, a conopeptide with high analgesic activity derived from Conus striatus. J. Nat. Prod., 2003, 66(9), 1276-1279.
[http://dx.doi.org/10.1021/np030099y] [PMID: 14510617]
[37]
Yan, L.D.; Liu, Y.L.; Zhang, L.; Dong, H.J.; Zhou, P.L.; Su, R.B.; Gong, Z.H.; Huang, P.T. Spinal antinociception of synthetic omega-conotoxin SO-3, a selective N-type neuronal voltage-sensitive calcium channel blocker, and its effects on morphine analgesia in chemical stimulus tests in rodent. Eur. J. Pharmacol., 2010, 636(1-3), 73-81.
[http://dx.doi.org/10.1016/j.ejphar.2010.03.036] [PMID: 20361956]
[38]
Wang, X.; Xie, L.P.; Li, Q.A.; Zhang, R.Q.; Zhou, X.W.; Huang, P.T. Effect of O-superfamily conotoxin SO3 on synchronized spontaneous calcium spikes in cultured hippocampal networks. Cell Biol. Toxicol., 2008, 24(1), 11-17.
[http://dx.doi.org/10.1007/s10565-007-9011-4] [PMID: 17522958]
[39]
Wang, F.; Yan, Z.; Liu, Z.; Wang, S.; Wu, Q.; Yu, S.; Ding, J.; Dai, Q. Molecular basis of toxicity of N-type calcium channel inhibitor MVIIA. Neuropharmacology, 2016, 101, 137-145.
[http://dx.doi.org/10.1016/j.neuropharm.2015.08.047] [PMID: 26344359]
[40]
Lewis, R.J.; Nielsen, K.J.; Craik, D.J.; Loughnan, M.L.; Adams, D.A.; Sharpe, I.A.; Luchian, T.; Adams, D.J.; Bond, T.; Thomas, L.; Jones, A.; Matheson, J.L.; Drinkwater, R.; Andrews, P.R.; Alewood, P.F. Novel omega-conotoxins from Conus catus discriminate among neuronal calcium channel subtypes. J. Biol. Chem., 2000, 275(45), 35335-35344.
[http://dx.doi.org/10.1074/jbc.M002252200] [PMID: 10938268]
[41]
Scott, D.A.; Wright, C.E.; Angus, J.A. Actions of intrathecal ω-conotoxins CVID, GVIA, MVIIA, and morphine in acute and neuropathic pain in the rat. Eur. J. Pharmacol., 2002, 451(3), 279-286.
[http://dx.doi.org/10.1016/S0014-2999(02)02247-1] [PMID: 12242089]
[42]
Kolosov, A.; Goodchild, C.S.; Cooke, I. CNSB004 (Leconotide) causes antihyperalgesia without side effects when given intravenously: A comparison with ziconotide in a rat model of diabetic neuropathic pain. Pain Med., 2010, 11(2), 262-273.
[http://dx.doi.org/10.1111/j.1526-4637.2009.00741.x] [PMID: 20002322]
[43]
Jayamanne, A.; Jeong, H.J.; Schroeder, C.I.; Lewis, R.J.; Christie, M.J.; Vaughan, C.W. Spinal actions of ω-conotoxins, CVID, MVIIA and related peptides in a rat neuropathic pain model. Br. J. Pharmacol., 2013, 170(2), 245-254.
[http://dx.doi.org/10.1111/bph.12251] [PMID: 23713957]
[44]
Berecki, G.; Motin, L.; Haythornthwaite, A.; Vink, S.; Bansal, P.; Drinkwater, R.; Wang, C.I.; Moretta, M.; Lewis, R.J.; Alewood, P.F.; Christie, M.J.; Adams, D.J. Analgesic (omega)-conotoxins CVIE and CVIF selectively and voltage-dependently block recombinant and native N-type calcium channels. Mol. Pharmacol., 2010, 77(2), 139-148.
[http://dx.doi.org/10.1124/mol.109.058834] [PMID: 19892914]
[45]
Sadeghi, M.; Murali, S.S.; Lewis, R.J.; Alewood, P.F.; Mohammadi, S.; Christie, M.J. Novel ω-conotoxins from C. catus reverse signs of mouse inflammatory pain after systemic administration. Mol. Pain, 2013, 9, 1744-8069-9-51.
[http://dx.doi.org/10.1186/1744-8069-9-51] [PMID: 24139484]
[46]
Berecki, G.; Daly, N.L.; Huang, Y.H.; Vink, S.; Craik, D.J.; Alewood, P.F.; Adams, D.J. Effects of arginine 10 to lysine substitution on ω-conotoxin CVIE and CVIF block of CA V 2.2 channels. Br. J. Pharmacol., 2014, 171(13), 3313-3327.
[http://dx.doi.org/10.1111/bph.12686] [PMID: 24628243]
[47]
Lee, S.; Kim, Y.; Back, S.K.; Choi, H.W.; Lee, J.Y.; Jung, H.H.; Ryu, J.H.; Suh, H.W.; Na, H.S.; Kim, H.J.; Rhim, H.; Kim, J.I. Analgesic effect of highly reversible ω-conotoxin FVIA on N type Ca2+ channels. Mol. Pain, 2010, 6, 1744-8069-6-97.
[http://dx.doi.org/10.1186/1744-8069-6-97] [PMID: 21172037]
[48]
Hu, H.; Bandyopadhyay, P.K.; Olivera, B.M.; Yandell, M. Characterization of the Conus bullatus genome and its venom-duct transcriptome. BMC Genomics, 2011, 12(1), 60.
[http://dx.doi.org/10.1186/1471-2164-12-60] [PMID: 21266071]
[49]
Chen, J.; Liu, X.; Yu, S.; Liu, J.; Chen, R.; Zhang, Y.; Jiang, L.; Dai, Q. A novel ω-conotoxin Bu8 inhibiting N-type voltage-gated calcium channels displays potent analgesic activity. Acta Pharm. Sin. B, 2021, 11(9), 2685-2693.
[http://dx.doi.org/10.1016/j.apsb.2021.03.001] [PMID: 34589389]
[50]
Sousa, S.R.; McArthur, J.R.; Brust, A.; Bhola, R.F.; Rosengren, K.J.; Ragnarsson, L.; Dutertre, S.; Alewood, P.F.; Christie, M.J.; Adams, D.J.; Vetter, I.; Lewis, R.J. Novel analgesic ω-conotoxins from the vermivorous cone snail Conus moncuri provide new insights into the evolution of conopeptides. Sci. Rep., 2018, 8(1), 13397.
[http://dx.doi.org/10.1038/s41598-018-31245-4] [PMID: 30194442]
[51]
Jimenéz, E.C.; Olivera, B.M.; Gray, W.R.; Cruz, L.J. Contryphan is a D-tryptophan-containing Conus peptide. J. Biol. Chem., 1996, 271(45), 28002-28005.
[http://dx.doi.org/10.1074/jbc.271.45.28002] [PMID: 8910408]
[52]
Hansson, K.; Ma, X.; Eliasson, L.; Czerwiec, E.; Furie, B.; Furie, B.C.; Rorsman, P.; Stenflo, J. The first gamma-carboxyglutamic acid-containing contryphan. A selective L-type calcium ion channel blocker isolated from the venom of Conus marmoreus. J. Biol. Chem., 2004, 279(31), 32453-32463.
[http://dx.doi.org/10.1074/jbc.M313825200] [PMID: 15155730]
[53]
Grant, M.A.; Hansson, K.; Furie, B.C.; Furie, B.; Stenflo, J.; Rigby, A.C. The metal-free and calcium-bound structures of a gamma-carboxyglutamic acid-containing contryphan from Conus marmoreus, glacontryphan-M. J. Biol. Chem., 2004, 279(31), 32464-32473.
[http://dx.doi.org/10.1074/jbc.M313826200] [PMID: 15155731]
[54]
Sabareesh, V.; Gowd, K.H.; Ramasamy, P.; Sudarslal, S.; Krishnan, K.S.; Sikdar, S.K.; Balaram, P. Characterization of contryphans from Conus loroisii and Conus amadis that target calcium channels. Peptides, 2006, 27(11), 2647-2654.
[http://dx.doi.org/10.1016/j.peptides.2006.07.009] [PMID: 16945451]
[55]
Cruz, L.J.; Gray, W.R.; Olivera, B.M.; Zeikus, R.D.; Kerr, L.; Yoshikami, D.; Moczydlowski, E. Conus geographus toxins that discriminate between neuronal and muscle sodium channels. J. Biol. Chem., 1985, 260(16), 9280-9288.
[http://dx.doi.org/10.1016/S0021-9258(17)39364-X] [PMID: 2410412]
[56]
Han, P.; Wang, K.; Dai, X.; Cao, Y.; Liu, S.; Jiang, H.; Fan, C.; Wu, W.; Chen, J. The role of individual disulfide bonds of μ-conotoxin GIIIA in the inhibition of Nav1.4. Mar. Drugs, 2016, 14(11), 213.
[http://dx.doi.org/10.3390/md14110213] [PMID: 27869701]
[57]
Bulaj, G.; West, P.J.; Garrett, J.E.; Watkins, M.; Zhang, M.M.; Norton, R.S.; Smith, B.J.; Yoshikami, D.; Olivera, B.M. Novel conotoxins from Conus striatus and Conus kinoshitai selectively block TTX-resistant sodium channels. Biochemistry, 2005, 44(19), 7259-7265.
[http://dx.doi.org/10.1021/bi0473408] [PMID: 15882064]
[58]
Schroeder, C.I.; Ekberg, J.; Nielsen, K.J.; Adams, D.; Loughnan, M.L.; Thomas, L.; Adams, D.J.; Alewood, P.F.; Lewis, R.J. Neuronally micro-conotoxins from Conus striatus utilize an alpha-helical motif to target mammalian sodium channels. J. Biol. Chem., 2008, 283(31), 21621-21628.
[http://dx.doi.org/10.1074/jbc.M802852200] [PMID: 18522941]
[59]
Yao, S.; Zhang, M.M.; Yoshikami, D.; Azam, L.; Olivera, B.M.; Bulaj, G.; Norton, R.S. Structure, dynamics, and selectivity of the sodium channel blocker μ-conotoxin SIIIA. Biochemistry, 2008, 47(41), 10940-10949.
[http://dx.doi.org/10.1021/bi801010u] [PMID: 18798648]
[60]
Zhang, M.M.; Green, B.R.; Catlin, P.; Fiedler, B.; Azam, L.; Chadwick, A.; Terlau, H.; McArthur, J.R.; French, R.J.; Gulyas, J.; Rivier, J.E.; Smith, B.J.; Norton, R.S.; Olivera, B.M.; Yoshikami, D.; Bulaj, G. Structure/function characterization of micro-conotoxin KIIIA, an analgesic, nearly irreversible blocker of mammalian neuronal sodium channels. J. Biol. Chem., 2007, 282(42), 30699-30706.
[http://dx.doi.org/10.1074/jbc.M704616200] [PMID: 17724025]
[61]
McArthur, J.R.; Singh, G.; McMaster, D.; Winkfein, R.; Tieleman, D.P.; French, R.J. Interactions of key charged residues contributing to selective block of neuronal sodium channels by μ-conotoxin KIIIA. Mol. Pharmacol., 2011, 80(4), 573-584.
[http://dx.doi.org/10.1124/mol.111.073460] [PMID: 21709136]
[62]
Pan, X.; Li, Z.; Huang, X.; Huang, G.; Gao, S.; Shen, H.; Liu, L.; Lei, J.; Yan, N. Molecular basis for pore blockade of human Na + channel Na v 1.2 by the μ-conotoxin KIIIA. Science, 2019, 363(6433), 1309-1313.
[http://dx.doi.org/10.1126/science.aaw2999] [PMID: 30765605]
[63]
Zhao, Z.; Pan, T.; Chen, S.; Harvey, P.J.; Zhang, J.; Li, X.; Yang, M.; Huang, L.; Wang, S.; Craik, D.J.; Jiang, T.; Yu, R. Design, synthesis, and mechanism of action of novel μ-conotoxin KIIIA analogues for inhibition of the voltage-gated sodium channel Nav1.7. J. Biol. Chem., 2023, 299(4), 103068.
[http://dx.doi.org/10.1016/j.jbc.2023.103068] [PMID: 36842500]
[64]
Lewis, R.J.; Schroeder, C.I.; Ekberg, J.; Nielsen, K.J.; Loughnan, M.; Thomas, L.; Adams, D.A.; Drinkwater, R.; Adams, D.J.; Alewood, P.F. Isolation and structure-activity of mu-conotoxin TIIIA, a potent inhibitor of tetrodotoxin-sensitive voltage-gated sodium channels. Mol. Pharmacol., 2007, 71(3), 676-685.
[http://dx.doi.org/10.1124/mol.106.028225] [PMID: 17142296]
[65]
Wilson, M.J.; Yoshikami, D.; Azam, L.; Gajewiak, J.; Olivera, B.M.; Bulaj, G.; Zhang, M.M. μ-Conotoxins that differentially block sodium channels Na V 1.1 through 1.8 identify those responsible for action potentials in sciatic nerve. Proc. Natl. Acad. Sci. USA, 2011, 108(25), 10302-10307.
[http://dx.doi.org/10.1073/pnas.1107027108] [PMID: 21652775]
[66]
Walewska, A.; Skalicky, J.J.; Davis, D.R.; Zhang, M.M.; López-Vera, E.; Watkins, M.; Han, T.S.; Yoshikami, D.; Olivera, B.M.; Bulaj, G. NMR-based mapping of disulfide bridges in cysteine-rich peptides: Application to the mu-conotoxin SxIIIA. J. Am. Chem. Soc., 2008, 130(43), 14280-14286.
[http://dx.doi.org/10.1021/ja804303p] [PMID: 18831583]
[67]
Wilson, M.J.; Zhang, M.M.; Gajewiak, J.; Azam, L.; Rivier, J.E.; Olivera, B.M.; Yoshikami, D. α- And β-subunit composition of voltage-gated sodium channels investigated with μ-conotoxins and the recently discovered μO§-conotoxin GVIIJ. J. Neurophysiol., 2015, 113(7), 2289-2301.
[http://dx.doi.org/10.1152/jn.01004.2014] [PMID: 25632083]
[68]
McMahon, K.L.; Tran, H.N.T.; Deuis, J.R.; Lewis, R.J.; Vetter, I.; Schroeder, C.I. Discovery, pharmacological characterisation and NMR structure of the novel µ-conotoxin SxIIIC, a potent and irreversible Nav channel inhibitor. Biomedicines, 2020, 8(10), 391.
[http://dx.doi.org/10.3390/biomedicines8100391] [PMID: 33023152]
[69]
Holford, M.; Zhang, M.M.; Gowd, K.H.; Azam, L.; Green, B.R.; Watkins, M.; Ownby, J.P.; Yoshikami, D.; Bulaj, G.; Olivera, B.M. Pruning nature: Biodiversity-derived discovery of novel sodium channel blocking conotoxins from Conus bullatus. Toxicon, 2009, 53(1), 90-98.
[http://dx.doi.org/10.1016/j.toxicon.2008.10.017] [PMID: 18950653]
[70]
Yang, M.; Zhao, S.; Min, X.; Shao, M.; Chen, Y.; Chen, Z.; Zhou, M. A novel μ-conotoxin from worm-hunting Conus tessulatus that selectively inhibit rat TTX-resistant sodium currents. Toxicon, 2017, 130, 11-18.
[http://dx.doi.org/10.1016/j.toxicon.2017.02.013] [PMID: 28219625]
[71]
McIntosh, J.M.; Hasson, A.; Spira, M.E.; Gray, W.R.; Li, W.; Marsh, M.; Hillyard, D.R.; Olivera, B.M. A new family of conotoxins that blocks voltage-gated sodium channels. J. Biol. Chem., 1995, 270(28), 16796-16802.
[http://dx.doi.org/10.1074/jbc.270.28.16796] [PMID: 7622492]
[72]
Zorn, S.; Leipold, E.; Hansel, A.; Bulaj, G.; Olivera, B.M.; Terlau, H.; Heinemann, S.H. The μO-conotoxin MrVIA inhibits voltage-gated sodium channels by associating with domain-3. FEBS Lett., 2006, 580(5), 1360-1364.
[http://dx.doi.org/10.1016/j.febslet.2006.01.057] [PMID: 16458302]
[73]
Bulaj, G.; Zhang, M.M.; Green, B.R.; Fiedler, B.; Layer, R.T.; Wei, S.; Nielsen, J.S.; Low, S.J.; Klein, B.D.; Wagstaff, J.D.; Chicoine, L.; Harty, T.P.; Terlau, H.; Yoshikami, D.; Olivera, B.M. Synthetic muO-conotoxin MrVIB blocks TTX-resistant sodium channel NaV1.8 and has a long-lasting analgesic activity. Biochemistry, 2006, 45(23), 7404-7414.
[http://dx.doi.org/10.1021/bi060159+] [PMID: 16752929]
[74]
Ekberg, J.; Jayamanne, A.; Vaughan, C.W.; Aslan, S.; Thomas, L.; Mould, J.; Drinkwater, R.; Baker, M.D.; Abrahamsen, B.; Wood, J.N.; Adams, D.J.; Christie, M.J.; Lewis, R.J. μO-conotoxin MrVIB selectively blocks Na v 1.8 sensory neuron specific sodium channels and chronic pain behavior without motor deficits. Proc. Natl. Acad. Sci. USA, 2006, 103(45), 17030-17035.
[http://dx.doi.org/10.1073/pnas.0601819103] [PMID: 17077153]
[75]
Wilson, M.J.; Zhang, M.M.; Azam, L.; Olivera, B.M.; Bulaj, G.; Yoshikami, D. Navβ subunits modulate the inhibition of Nav1.8 by the analgesic gating modifier μO-conotoxin MrVIB. J. Pharmacol. Exp. Ther., 2011, 338(2), 687-693.
[http://dx.doi.org/10.1124/jpet.110.178343] [PMID: 21586605]
[76]
Knapp, O.; Nevin, S.T.; Yasuda, T.; Lawrence, N.; Lewis, R.J.; Adams, D.J. Biophysical properties of Na v 1.8/Na v 1.2 chimeras and inhibition by µO-conotoxin MrVIB. Br. J. Pharmacol., 2012, 166(7), 2148-2160.
[http://dx.doi.org/10.1111/j.1476-5381.2012.01955.x] [PMID: 22452751]
[77]
Vetter, I.; Dekan, Z.; Knapp, O.; Adams, D.J.; Alewood, P.F.; Lewis, R.J. Isolation, characterization and total regioselective synthesis of the novel μO-conotoxin MfVIA from Conus magnificus that targets voltage-gated sodium channels. Biochem. Pharmacol., 2012, 84(4), 540-548.
[http://dx.doi.org/10.1016/j.bcp.2012.05.008] [PMID: 22609441]
[78]
Wang, L.; Liu, J.; Ren, Z.; Chen, Y.; Xu, A. Discovery of two P-superfamily conotoxins, lt9a and lt9b, with different modifications on voltage-sensitive sodium channels. Toxicon, 2017, 134, 6-13.
[http://dx.doi.org/10.1016/j.toxicon.2017.05.020] [PMID: 28533144]
[79]
Barbier, J.; Lamthanh, H.; Le Gall, F.; Favreau, P.; Benoit, E.; Chen, H.; Gilles, N.; Ilan, N.; Heinemann, S.H.; Gordon, D.; Ménez, A.; Molgó, J. A delta-conotoxin from Conus ermineus venom inhibits inactivation in vertebrate neuronal Na+ channels but not in skeletal and cardiac muscles. J. Biol. Chem., 2004, 279(6), 4680-4685.
[http://dx.doi.org/10.1074/jbc.M309576200] [PMID: 14615484]
[80]
Jin, AH; Israel, MR; Inserra, MC; Smith, JJ; Lewis, RJ; Alewood, PF δ-Conotoxin SuVIA suggests an evolutionary link between ancestral predator defense and the origin of fish-hunting behaviour in carnivorous cone snails. Proc Biol Sci., 2015, 282(1811), 0817.
[81]
Aman, J.W.; Imperial, J.S.; Ueberheide, B.; Zhang, M.M.; Aguilar, M.; Taylor, D.; Watkins, M.; Yoshikami, D.; Showers-Corneli, P.; Safavi-Hemami, H.; Biggs, J.; Teichert, R.W.; Olivera, B.M. Insights into the origins of fish hunting in venomous cone snails from studies of Conus tessulatus. Proc. Natl. Acad. Sci., 2015, 112(16), 5087-5092.
[http://dx.doi.org/10.1073/pnas.1424435112] [PMID: 25848010]
[82]
Jimenez, E.C.; Shetty, R.P.; Lirazan, M.; Rivier, J.; Walker, C.; Abogadie, F.C.; Yoshikami, D.; Cruz, L.J.; Olivera, B.M. Novel excitatory Conus peptides define a new conotoxin superfamily. J. Neurochem., 2003, 85(3), 610-621.
[http://dx.doi.org/10.1046/j.1471-4159.2003.01685.x] [PMID: 12694387]
[83]
Buczek, O.; Yoshikami, D.; Bulaj, G.; Jimenez, E.C.; Olivera, B.M. Post-translational amino acid isomerization: A functionally important D-amino acid in an excitatory peptide. J. Biol. Chem., 2005, 280(6), 4247-4253.
[http://dx.doi.org/10.1074/jbc.M405835200] [PMID: 15561705]
[84]
Buczek, O.; Wei, D.; Babon, J.J.; Yang, X.; Fiedler, B.; Chen, P.; Yoshikami, D.; Olivera, B.M.; Bulaj, G.; Norton, R.S. Structure and sodium channel activity of an excitatory I1-superfamily conotoxin. Biochemistry, 2007, 46(35), 9929-9940.
[http://dx.doi.org/10.1021/bi700797f] [PMID: 17696362]
[85]
Fiedler, B.; Zhang, M.M.; Buczek, O.; Azam, L.; Bulaj, G.; Norton, R.S.; Olivera, B.M.; Yoshikami, D. Specificity, affinity and efficacy of iota-conotoxin RXIA, an agonist of voltage-gated sodium channels Na(V)1.2, 1.6 and 1.7. Biochem. Pharmacol., 2008, 75(12), 2334-2344.
[http://dx.doi.org/10.1016/j.bcp.2008.03.019] [PMID: 18486102]
[86]
Terlau, H.; Shon, K.J.; Grilley, M.; Stocker, M.; Stühmer, W.; Olivera, B.M. Strategy for rapid immobilization of prey by a fish-hunting marine snail. Nature, 1996, 381(6578), 148-151.
[http://dx.doi.org/10.1038/381148a0] [PMID: 12074021]
[87]
Jacobsen, R.B.; Koch, E.D.; Lange-Malecki, B.; Stocker, M.; Verhey, J.; Van Wagoner, R.M.; Vyazovkina, A.; Olivera, B.M.; Terlau, H. Single amino acid substitutions in kappa-conotoxin PVIIA disrupt interaction with the shaker K+ channel. J. Biol. Chem., 2000, 275(32), 24639-24644.
[http://dx.doi.org/10.1074/jbc.C900990199] [PMID: 10818087]
[88]
Boccaccio, A.; Conti, F.; Olivera, B.M.; Terlau, H. Binding of kappa-conotoxin PVIIA to Shaker K+ channels reveals different K+ and Rb+ occupancies within the ion channel pore. J. Gen. Physiol., 2004, 124(1), 71-81.
[http://dx.doi.org/10.1085/jgp.200409048] [PMID: 15226365]
[89]
Lubbers, N.L.; Campbell, T.J.; Polakowski, J.S.; Bulaj, G.; Layer, R.T.; Moore, J.; Gross, G.J.; Cox, B.F. Postischemic administration of CGX-1051, a peptide from cone snail venom, reduces infarct size in both rat and dog models of myocardial ischemia and reperfusion. J. Cardiovasc. Pharmacol., 2005, 46(2), 141-146.
[http://dx.doi.org/10.1097/01.fjc.0000167015.84715.27] [PMID: 16044024]
[90]
Naranjo, D.; Díaz-Franulic, I. Binding of κ-Conotoxin-PVIIA to open and closed Shaker K+ channels are differentially affected by the ionic strength. Mar. Drugs, 2020, 18(11), 533.
[http://dx.doi.org/10.3390/md18110533] [PMID: 33114777]
[91]
Fan, C.X.; Chen, X.K.; Zhang, C.; Wang, L.X.; Duan, K.L.; He, L.L.; Cao, Y.; Liu, S.Y.; Zhong, M.N.; Ulens, C.; Tytgat, J.; Chen, J.S.; Chi, C.W.; Zhou, Z. A novel conotoxin from Conus betulinus, kappa-BtX, unique in cysteine pattern and in function as a specific BK channel modulator. J. Biol. Chem., 2003, 278(15), 12624-12633.
[http://dx.doi.org/10.1074/jbc.M210200200] [PMID: 12547831]
[92]
Ferber, M.; Sporning, A.; Jeserich, G.; DeLaCruz, R.; Watkins, M.; Olivera, B.M.; Terlau, H. A novel conus peptide ligand for K+ channels. J. Biol. Chem., 2003, 278(4), 2177-2183.
[http://dx.doi.org/10.1074/jbc.M205953200] [PMID: 12399472]
[93]
Ferber, M.; Al-Sabi, A.; Stocker, M.; Olivera, B.M.; Terlau, H. Identification of a mammalian target of κM-conotoxin RIIIK. Toxicon, 2004, 43(8), 915-921.
[http://dx.doi.org/10.1016/j.toxicon.2003.12.010] [PMID: 15208025]
[94]
Al-Sabi, A.; Lennartz, D.; Ferber, M.; Gulyas, J.; Rivier, J.E.F.; Olivera, B.M.; Carlomagno, T.; Terlau, H. KappaM-conotoxin RIIIK, structural and functional novelty in a K+ channel antagonist. Biochemistry, 2004, 43(27), 8625-8635.
[http://dx.doi.org/10.1021/bi0495681] [PMID: 15236570]
[95]
Verdier, L.; Al-Sabi, A.; Rivier, J.E.F.; Olivera, B.M.; Terlau, H.; Carlomagno, T. Identification of a novel pharmacophore for peptide toxins interacting with K+ channels. J. Biol. Chem., 2005, 280(22), 21246-21255.
[http://dx.doi.org/10.1074/jbc.M502376200] [PMID: 15799976]
[96]
Chen, P.; Dendorfer, A.; Finol-Urdaneta, R.K.; Terlau, H.; Olivera, B.M. Biochemical characterization of kappaM-RIIIJ, a Kv1.2 channel blocker: Evaluation of cardioprotective effects of kappaM-conotoxins. J. Biol. Chem., 2010, 285(20), 14882-14889.
[http://dx.doi.org/10.1074/jbc.M109.068486] [PMID: 20220134]
[97]
Cordeiro, S.; Finol-Urdaneta, R.K.; Köpfer, D.; Markushina, A.; Song, J.; French, R.J.; Kopec, W.; de Groot, B.L.; Giacobassi, M.J.; Leavitt, L.S.; Raghuraman, S.; Teichert, R.W.; Olivera, B.M.; Terlau, H. Conotoxin κM-RIIIJ, a tool targeting asymmetric heteromeric Kv1 channels. Proc. Natl. Acad. Sci. USA, 2019, 116(3), 1059-1064.
[http://dx.doi.org/10.1073/pnas.1813161116] [PMID: 30593566]
[98]
Martínez-Hernández, L.; López-Vera, E.; Aguilar, M.B.; Rodriguez-Ruiz, X.C.; Ortíz-Arellano, M.A. κO-SrVIA conopeptide, a novel inhibitor peptide for two members of the human EAG potassium channel family. Int. J. Mol. Sci., 2023, 24(14), 11513.
[http://dx.doi.org/10.3390/ijms241411513] [PMID: 37511269]
[99]
Bayrhuber, M.; Vijayan, V.; Ferber, M.; Graf, R.; Korukottu, J.; Imperial, J.; Garrett, J.E.; Olivera, B.M.; Terlau, H.; Zweckstetter, M.; Becker, S. Conkunitzin-S1 is the first member of a new Kunitz-type neurotoxin family. Structural and functional characterization. J. Biol. Chem., 2005, 280(25), 23766-23770.
[http://dx.doi.org/10.1074/jbc.C500064200] [PMID: 15833744]
[100]
Finol-Urdaneta, R.K.; Remedi, M.S.; Raasch, W.; Becker, S.; Clark, R.B.; Strüver, N.; Pavlov, E.; Nichols, C.G.; French, R.J.; Terlau, H. Block of K v 1.7 potassium currents increases glucose-stimulated insulin secretion. EMBO Mol. Med., 2012, 4(5), 424-434.
[http://dx.doi.org/10.1002/emmm.201200218] [PMID: 22438204]
[101]
Violette, A.; Biass, D.; Dutertre, S.; Koua, D.; Piquemal, D.; Pierrat, F.; Stöcklin, R.; Favreau, P. Large-scale discovery of conopeptides and conoproteins in the injectable venom of a fish-hunting cone snail using a combined proteomic and transcriptomic approach. J. Proteomics, 2012, 75(17), 5215-5225.
[http://dx.doi.org/10.1016/j.jprot.2012.06.001] [PMID: 22705119]
[102]
Saikia, C.; Dym, O.; Altman-Gueta, H.; Gordon, D.; Reuveny, E.; Karbat, I. A molecular lid mechanism of K+ channel blocker action revealed by a cone peptide. J. Mol. Biol., 2021, 433(17), 166957.
[http://dx.doi.org/10.1016/j.jmb.2021.166957] [PMID: 33771569]
[103]
Campos-Lira, E.; Carrillo, E.; Aguilar, M.B.; Gajewiak, J.; Gómez-Lagunas, F.; López-Vera, E. Conorfamide-Sr3, a structurally novel specific inhibitor of the Shaker K+ channel. Toxicon, 2017, 138, 53-58.
[http://dx.doi.org/10.1016/j.toxicon.2017.07.024] [PMID: 28774677]
[104]
López-Vera, E.; Martínez-Hernández, L.; Aguilar, M.B.; Carrillo, E.; Gajewiak, J. Studies of conorfamide-Sr3 on human voltage-gated Kv1 potassium channel subtypes. Mar. Drugs, 2020, 18(8), 425.
[http://dx.doi.org/10.3390/md18080425] [PMID: 32823677]
[105]
Catterall, W.A.; Swanson, T.M. Structural basis for pharmacology of voltage-gated sodium and calcium channels. Mol. Pharmacol., 2015, 88(1), 141-150.
[http://dx.doi.org/10.1124/mol.114.097659] [PMID: 25848093]
[106]
González, C.; Baez-Nieto, D.; Valencia, I.; Oyarzún, I.; Rojas, P.; Naranjo, D.; Latorre, R. K(+) channels: Function-structural overview. Compr. Physiol., 2012, 2(3), 2087-2149.
[http://dx.doi.org/10.1002/cphy.c110047] [PMID: 23723034]
[107]
Chalil, A.; Staudt, M.D.; Harland, T.A.; Leimer, E.M.; Bhullar, R.; Argoff, C.E. A safety review of approved intrathecal analgesics for chronic pain management. Expert Opin. Drug Saf., 2021, 20(4), 439-451.
[http://dx.doi.org/10.1080/14740338.2021.1889513] [PMID: 33583318]
[108]
Sameera; Shah, F.A.; Rashid, S. Conformational ensembles of non-peptide ω-conotoxin mimetics and Ca+2 ion binding to human voltage-gated N-type calcium channel Cav2.2. Comput. Struct. Biotechnol. J., 2020, 18, 2357-2372.
[http://dx.doi.org/10.1016/j.csbj.2020.08.027] [PMID: 32994894]
[109]
Gao, S.; Yao, X.; Yan, N. Structure of human Cav2.2 channel blocked by the painkiller ziconotide. Nature, 2021, 596(7870), 143-147.
[http://dx.doi.org/10.1038/s41586-021-03699-6] [PMID: 34234349]
[110]
Mollica, A.; Costante, R.; Novellino, E.; Stefanucci, A.; Pieretti, S.; Zador, F.; Samavati, R.; Borsodi, A.; Benyhe, S.; Vetter, I.; Lewis, R.J. Design, synthesis and biological evaluation of two opioid agonist and Cav 2.2 blocker multitarget ligands. Chem. Biol. Drug Des., 2015, 86(2), 156-162.
[http://dx.doi.org/10.1111/cbdd.12479] [PMID: 25393330]
[111]
Wu, L.; Lin, W.; Liao, Q.; Wang, H.; Lin, C.; Tang, L.; Lian, W.; Chen, Z.; Li, K.; Xu, L.; Zhou, R.; Ding, Y.; Zhao, L. Calcium channel blocker nifedipine suppresses colorectal cancer progression and immune escape by preventing NFAT2 nuclear translocation. Cell Rep., 2020, 33(4), 108327.
[http://dx.doi.org/10.1016/j.celrep.2020.108327] [PMID: 33113363]
[112]
Roberson, D.P.; Binshtok, A.M.; Blasl, F.; Bean, B.P.; Woolf, C.J. Targeting of sodium channel blockers into nociceptors to produce long-duration analgesia: A systematic study and review. Br. J. Pharmacol., 2011, 164(1), 48-58.
[http://dx.doi.org/10.1111/j.1476-5381.2011.01391.x] [PMID: 21457220]
[113]
Ingleby-Talecki, L.; van Dijkman, S.C.; Oosterholt, S.P.; Della Pasqua, O.; Winter, C.; Cunnington, M.; Rebar, L.; Forero-Schwanhaeuser, S.; Patel, V.; Cooper, J.A.; Bahinski, A.; Chaudhary, K.W. Cardiac sodium channel inhibition by lamotrigine: In vitro characterization and clinical implications. Clin. Transl. Sci., 2022, 15(8), 1978-1989.
[http://dx.doi.org/10.1111/cts.13311] [PMID: 35579204]
[114]
Riera, A.R.P.; Uchida, A.H.; Ferreira, C.; Ferreira Filho, C.; Schapachnik, E.; Dubner, S.; Zhang, L.; Moffa, P.J. Relationship among amiodarone, new class III antiarrhythmics, miscellaneous agents and acquired long QT syndrome. Cardiol. J., 2008, 15(3), 209-219.
[PMID: 18651412]
[115]
Zhang, S.; Yang, L.; Zhang, K.; Liu, X.; Dai, W.; Zhang, C.; Yong, Z.; Li, J.; Zheng, J. ZC88, a novel N-type calcium channel blocker from 4-amino-piperidine derivatives state-dependent inhibits Cav2.2 calcium channels. Brain Res., 2015, 1605, 12-21.
[http://dx.doi.org/10.1016/j.brainres.2015.01.054] [PMID: 25681549]

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