{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T13:01:53Z","timestamp":1788267713398,"version":"build-2803163510"},"reference-count":68,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,2,6]],"date-time":"2021-02-06T00:00:00Z","timestamp":1612569600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,2,6]],"date-time":"2021-02-06T00:00:00Z","timestamp":1612569600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Ministry of Finance, Hungary","award":["GINOP-2.3.2-15-2016-00015"],"award-info":[{"award-number":["GINOP-2.3.2-15-2016-00015"]}]},{"DOI":"10.13039\/501100005881","name":"Emberi Eroforr\u00e1sok Miniszt\u00e9riuma","doi-asserted-by":"crossref","award":["EFOP-3.6.2-16-2017-00006"],"award-info":[{"award-number":["EFOP-3.6.2-16-2017-00006"]}],"id":[{"id":"10.13039\/501100005881","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100011019","name":"NKFIH","doi-asserted-by":"crossref","award":["K119417"],"award-info":[{"award-number":["K119417"]}],"id":[{"id":"10.13039\/501100011019","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100009232","name":"University of Debrecen","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100009232","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BIOLOGIA FUTURA"],"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Since the discovery of the Kv1.3 voltage-gated K<jats:sup>+<\/jats:sup> channel in human T cells in 1984, ion channels are considered crucial elements of the signal transduction machinery in the immune system. Our knowledge about Kv1.3 and its inhibitors is outstanding, motivated by their potential application in autoimmune diseases mediated by Kv1.3 overexpressing effector memory T cells (e.g., Multiple Sclerosis). High affinity Kv1.3 inhibitors are either small organic molecules (e.g., Pap-1) or peptides isolated from venomous animals. To date, the highest affinity Kv1.3 inhibitors with the best Kv1.3 selectivity are the engineered analogues of the sea anemone peptide ShK (e.g., ShK-186), the engineered scorpion toxin HsTx1[R14A] and the natural scorpion toxin Vm24. These peptides inhibit Kv1.3 in picomolar concentrations and are several thousand-fold selective for Kv1.3 over other biologically critical ion channels. Despite the significant progress in the field of Kv1.3 molecular pharmacology several progressive questions remain to be elucidated and discussed here. These include the conjugation of the peptides to carriers to increase the residency time of the peptides in the circulation (e.g., PEGylation and engineering the peptides into antibodies), use of rational drug design to create novel peptide inhibitors and understanding the potential off-target effects of Kv1.3 inhibition.<\/jats:p>","DOI":"10.1007\/s42977-021-00071-7","type":"journal-article","created":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T22:50:39Z","timestamp":1612824639000},"page":"75-83","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["The Kv1.3 K+ channel in the immune system and its \u201cprecision pharmacology\u201d using peptide toxins"],"prefix":"10.1007","volume":"72","author":[{"given":"Zoltan","family":"Varga","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabor","family":"Tajti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6227-3301","authenticated-orcid":false,"given":"Gyorgy","family":"Panyi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,2,6]]},"reference":[{"key":"71_CR1","first-page":"237","volume":"148","author":"XE Asuncion","year":"2019","unstructured":"Asuncion XE, Sampaco A-RB, Adorna H, Magadia J, Bo\u00d2golan VP, Lluisma A (2019) Predicting the molecular targets of conopeptides by using principal component analysis and multiclass logistic regression philippine. J Sci 148:237\u2013245","journal-title":"J Sci"},{"key":"71_CR2","doi-asserted-by":"publisher","first-page":"18397","DOI":"10.1038\/srep18397","volume":"5","author":"A Bartok","year":"2015","unstructured":"Bartok A, Feh\u00e9r K, Bodor A, R\u00e1kosi K, T\u00f3th GK, K\u00f6v\u00e9r KE, Panyi G, Varga Z (2015a) An engineered scorpion toxin analogue with improved Kv1.3 selectivity displays reduced conformational flexibility. Sci. Rep. 5:18397. https:\/\/doi.org\/10.1038\/srep18397","journal-title":"Sci. Rep."},{"key":"71_CR3","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1007\/978-94-007-6404-0_30","volume-title":"Scorpion venoms","author":"A Bartok","year":"2015","unstructured":"Bartok A, Panyi G, Varga Z (2015b) Potassium channel blocking peptide toxins from scorpion venom. In: Gopalakrishnakone P, Possani L, Schwartz EF, de la Vega RR (eds) Scorpion venoms, vol 4. Springer, Dordrecht, pp 493\u2013527"},{"key":"71_CR4","doi-asserted-by":"publisher","first-page":"1369","DOI":"10.1124\/mol.104.008193","volume":"67","author":"C Beeton","year":"2005","unstructured":"Beeton C, Pennington MW, Wulff H, Singh S, Nugent D, Crossley G, Khaytin I, Calabresi PA, Chen CY, Gutman GA, Chandy KG (2005) Targeting effector memory T cells with a selective peptide inhibitor of Kv1.3 channels for therapy of autoimmune diseases. Mol Pharmacol 67:1369\u20131381","journal-title":"Mol Pharmacol"},{"key":"71_CR5","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1111\/j.1600-065X.2009.00816.x","volume":"231","author":"MD Cahalan","year":"2009","unstructured":"Cahalan MD, Chandy KG (2009) The functional network of ion channels in T lymphocytes. Immunol Rev 231:59\u201387. https:\/\/doi.org\/10.1111\/j.1600-065X.2009.00816.x","journal-title":"Immunol Rev"},{"key":"71_CR6","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1084\/jem.160.2.369","volume":"160","author":"KG Chandy","year":"1984","unstructured":"Chandy KG, Decoursey TE, Cahalan MD, McLaughlin C, Gupta S (1984) Voltage-gated potassium channels are required for human T lymphocyte activation. J Exp Med 160:369\u2013385","journal-title":"J Exp Med"},{"key":"71_CR7","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.cbpa.2017.02.015","volume":"38","author":"KG Chandy","year":"2017","unstructured":"Chandy KG, Norton RS (2017) Peptide blockers of Kv1.3 channels in T cells as therapeutics for autoimmune disease. Curr Opin Chem Biol 38:97\u2013107. https:\/\/doi.org\/10.1016\/j.cbpa.2017.02.015","journal-title":"Curr Opin Chem Biol"},{"key":"71_CR8","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1016\/j.toxicon.2011.07.016","volume":"59","author":"V Chi","year":"2012","unstructured":"Chi V, Pennington MW, Norton RS, Tarcha EJ, Londono LM, Sims-Fahey B, Upadhyay SK, Lakey JT, Iadonato S, Wulff H, Beeton C, Chandy KG (2012) Development of a sea anemone toxin as an immunomodulator for therapy of autoimmune diseases. Toxicon 59:529\u2013546","journal-title":"Toxicon"},{"key":"71_CR9","doi-asserted-by":"publisher","first-page":"14644","DOI":"10.1038\/ncomms14644","volume":"8","author":"EY Chiang","year":"2017","unstructured":"Chiang EY, Li T, Jeet S, Peng I, Zhang J, Lee WP, DeVoss J, Caplazi P, Chen J, Warming S, Hackos DH, Mukund S, Koth CM, Grogan JL (2017) Potassium channels Kv1.3 and KCa3.1 cooperatively and compensatorily regulate antigen-specific memory T cell functions. Nat Commun 8:14644. https:\/\/doi.org\/10.1038\/ncomms14644","journal-title":"Nat Commun"},{"key":"71_CR10","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1007\/s12016-016-8582-3","volume":"52","author":"CB Chighizola","year":"2017","unstructured":"Chighizola CB, Ong VH, Meroni PL (2017) The use of cyclosporine A in rheumatology: a 2016 comprehensive review. Clin Rev Allergy Immunol 52:401\u2013423. https:\/\/doi.org\/10.1007\/s12016-016-8582-3","journal-title":"Clin Rev Allergy Immunol"},{"key":"71_CR11","doi-asserted-by":"publisher","first-page":"1711","DOI":"10.1007\/s00424-014-1607-y","volume":"467","author":"P Cidad","year":"2015","unstructured":"Cidad P, Miguel-Velado E, Ruiz-McDavitt C, Alonso E, Jimenez-Perez L, Asuaje A, Carmona Y, Garcia-Arribas D, Lopez J, Marroquin Y, Fernandez M, Roque M, Perez-Garcia MT, Lopez-Lopez JR (2015) Kv1.3 channels modulate human vascular smooth muscle cells proliferation independently of mTOR signaling pathway. Pflugers Arch 467:1711\u20131722. https:\/\/doi.org\/10.1007\/s00424-014-1607-y","journal-title":"Pflugers Arch"},{"key":"71_CR12","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1038\/sj.bjp.0702283","volume":"126","author":"S Diochot","year":"1999","unstructured":"Diochot S, Drici MD, Moinier D, Fink M, Lazdunski M (1999) Effects of phrixotoxins on the Kv4 family of potassium channels and implications for the role of Ito1 in cardiac electrogenesis. Br J Pharmacol 126:251\u2013263. https:\/\/doi.org\/10.1038\/sj.bjp.0702283","journal-title":"Br J Pharmacol"},{"key":"71_CR13","doi-asserted-by":"publisher","first-page":"1079","DOI":"10.1080\/14728222.2020.1820987","volume":"24","author":"G Fernandez-Ballester","year":"2020","unstructured":"Fernandez-Ballester G, Fernandez-Carvajal A, Ferrer-Montiel A (2020) Targeting thermo TRP ion channels: in silico preclinical approaches and opportunities. Expert Opin Ther Targets 24:1079\u20131097. https:\/\/doi.org\/10.1080\/14728222.2020.1820987","journal-title":"Expert Opin Ther Targets"},{"key":"71_CR14","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1084\/jem.20050687","volume":"202","author":"S Feske","year":"2005","unstructured":"Feske S, Prakriya M, Rao A, Lewis RS (2005) A severe defect in CRAC Ca2+ channel activation and altered K+ channel gating in T cells from immunodeficient patients. J Exp Med 202:651\u2013662","journal-title":"J Exp Med"},{"key":"71_CR15","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1038\/nri3233","volume":"12","author":"S Feske","year":"2012","unstructured":"Feske S, Skolnik EY, Prakriya M (2012) Ion channels and transporters in lymphocyte function and immunity. Nat Rev Immunol 12:532\u2013547. https:\/\/doi.org\/10.1038\/nri3233","journal-title":"Nat Rev Immunol"},{"key":"71_CR16","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1146\/annurev-immunol-032414-112212","volume":"33","author":"S Feske","year":"2015","unstructured":"Feske S, Wulff H, Skolnik EY (2015) Ion channels in innate and adaptive immunity. Annu Rev Immunol 33:291\u2013353. https:\/\/doi.org\/10.1146\/annurev-immunol-032414-112212","journal-title":"Annu Rev Immunol"},{"key":"71_CR17","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1152\/physrev.00035.2012","volume":"93","author":"D Gordon","year":"2013","unstructured":"Gordon D, Chen R, Chung SH (2013) Computational methods of studying the binding of toxins from venomous animals to biological ion channels: theory and applications. Physiol Rev 93:767\u2013802. https:\/\/doi.org\/10.1152\/physrev.00035.2012","journal-title":"Physiol Rev"},{"key":"71_CR18","doi-asserted-by":"publisher","first-page":"4049","DOI":"10.1021\/bi300060n","volume":"51","author":"GB Gurrola","year":"2012","unstructured":"Gurrola GB, Hernandez-Lopez RA, Rodriguez de la Vega RC, Varga Z, Batista CV, Salas-Castillo SP, Panyi G, del Rio-Portilla F, Possani LD (2012) Structure, function, and chemical synthesis of Vaejovis mexicanus peptide 24: a novel potent blocker of Kv1.3 potassium channels of human T lymphocytes. Biochemistry 51:4049\u20134061. https:\/\/doi.org\/10.1021\/bi300060n","journal-title":"Biochemistry"},{"key":"71_CR19","doi-asserted-by":"publisher","first-page":"2715","DOI":"10.1056\/NEJMra033540","volume":"351","author":"PF Halloran","year":"2004","unstructured":"Halloran PF (2004) Immunosuppressive drugs for kidney transplantation. N Engl J Med 351:2715\u20132729. https:\/\/doi.org\/10.1056\/NEJMra033540","journal-title":"N Engl J Med"},{"key":"71_CR20","doi-asserted-by":"publisher","DOI":"10.1016\/j.xphs.2020.10.014","author":"L Jin","year":"2020","unstructured":"Jin L, Pan Y, Pham AC, Boyd BJ, Norton RS, Nicolazzo JA (2020) Prolonged plasma exposure of the Kv1.3-inhibitory peptide HsTX1[R14A] by subcutaneous administration of a poly(lactic-co-glycolic acid) (PLGA) microsphere formulation. J Pharm Sci. https:\/\/doi.org\/10.1016\/j.xphs.2020.10.014","journal-title":"J Pharm Sci"},{"key":"71_CR21","doi-asserted-by":"publisher","first-page":"2159","DOI":"10.3390\/toxins7062159","volume":"7","author":"Q Kaas","year":"2015","unstructured":"Kaas Q, Craik DJ (2015) Bioinformatics-aided venomics. Toxins (Basel) 7:2159\u20132187. https:\/\/doi.org\/10.3390\/toxins7062159","journal-title":"Toxins (Basel)"},{"key":"71_CR22","doi-asserted-by":"publisher","first-page":"32697","DOI":"10.1074\/jbc.273.49.32697","volume":"273","author":"K Kalman","year":"1998","unstructured":"Kalman K, Pennington MW, Lanigan MD, Nguyen A, Rauer H, Mahnir V, Paschetto K, Kem WR, Grissmer S, Gutman GA, Christian EP, Cahalan MD, Norton RS, Chandy KG (1998) ShK-Dap22, a potent Kv1.3-specific immunosuppressive polypeptide. J Biol Chem 273:32697\u201332707","journal-title":"J Biol Chem"},{"key":"71_CR23","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1093\/clinids\/11.5.677","volume":"11","author":"JH Kim","year":"1989","unstructured":"Kim JH, Perfect JR (1989) Infection and cyclosporine. Rev Infect Dis 11:677\u2013690. https:\/\/doi.org\/10.1093\/clinids\/11.5.677","journal-title":"Rev Infect Dis"},{"key":"71_CR24","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.jaut.2014.07.003","volume":"55","author":"S Kundu-Raychaudhuri","year":"2014","unstructured":"Kundu-Raychaudhuri S, Chen YJ, Wulff H, Raychaudhuri SP (2014) Kv1.3 in psoriatic disease: PAP-1, a small molecule inhibitor of Kv1.3 is effective in the SCID mouse psoriasis\u2013xenograft model. J Autoimmun 55:63\u201372. https:\/\/doi.org\/10.1016\/j.jaut.2014.07.003","journal-title":"J Autoimmun"},{"key":"71_CR25","doi-asserted-by":"publisher","first-page":"468","DOI":"10.2174\/157015911796557939","volume":"9","author":"EC Lallana","year":"2011","unstructured":"Lallana EC, Fadul CE (2011) Toxicities of immunosuppressive treatment of autoimmune neurologic diseases. Curr Neuropharmacol 9:468\u2013477. https:\/\/doi.org\/10.2174\/157015911796557939","journal-title":"Curr Neuropharmacol"},{"key":"71_CR26","doi-asserted-by":"publisher","first-page":"1107","DOI":"10.1113\/JP274888","volume":"596","author":"C Lau","year":"2018","unstructured":"Lau C, Hunter MJ, Stewart A, Perozo E, Vandenberg JI (2018) Never at rest: insights into the conformational dynamics of ion channels from cryo-electron microscopy. J Physiol 596:1107\u20131119. https:\/\/doi.org\/10.1113\/JP274888","journal-title":"J Physiol"},{"issue":"Pt 1","key":"71_CR27","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1042\/bj3280321","volume":"328","author":"B Lebrun","year":"1997","unstructured":"Lebrun B, Romi-Lebrun R, Martin-Eauclaire MF, Yasuda A, Ishiguro M, Oyama Y, Pongs O, Nakajima T (1997) A four-disulphide-bridged toxin, with high affinity towards voltage-gated K+ channels, isolated from Heterometrus spinnifer (Scorpionidae) venom. Biochem J 328(Pt 1):321\u2013327","journal-title":"Biochem J"},{"key":"71_CR28","doi-asserted-by":"publisher","first-page":"1266","DOI":"10.1016\/j.imbio.2016.06.004","volume":"221","author":"N Legany","year":"2016","unstructured":"Legany N, Toldi G, Orban C, Megyes N, Bajnok A, Balog A (2016) Calcium influx kinetics, and the features of potassium channels of peripheral lymphocytes in primary Sjogren\u2019s syndrome. Immunobiology 221:1266\u20131272. https:\/\/doi.org\/10.1016\/j.imbio.2016.06.004","journal-title":"Immunobiology"},{"key":"71_CR29","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1038\/nbt0697-559","volume":"15","author":"M Li","year":"1997","unstructured":"Li M (1997) Use of a modified bacteriophage to probe the interactions between peptides and ion channel receptors in mammalian cells. Nat Biotechnol 15:559\u2013563. https:\/\/doi.org\/10.1038\/nbt0697-559","journal-title":"Nat Biotechnol"},{"key":"71_CR30","doi-asserted-by":"publisher","first-page":"e56375","DOI":"10.1371\/journal.pone.0056375","volume":"8","author":"H Lund","year":"2013","unstructured":"Lund H, Krakauer M, Skimminge A, Sellebjerg F, Garde E, Siebner HR, Paulson OB, Hesse D, Hanson LG (2013) Blood-brain barrier permeability of normal appearing white matter in relapsing-remitting multiple sclerosis. PLoS ONE 8:e56375. https:\/\/doi.org\/10.1371\/journal.pone.0056375","journal-title":"PLoS ONE"},{"key":"71_CR31","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1016\/j.drudis.2018.11.014","volume":"24","author":"KK Mak","year":"2019","unstructured":"Mak KK, Pichika MR (2019) Artificial intelligence in drug development: present status and future prospects. Drug Discov Today 24:773\u2013780. https:\/\/doi.org\/10.1016\/j.drudis.2018.11.014","journal-title":"Drug Discov Today"},{"key":"71_CR32","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1038\/307468a0","volume":"307","author":"DR Matteson","year":"1984","unstructured":"Matteson DR, Deutsch C (1984) K channels in T lymphocytes: a patch clamp study using monoclonal antibody adhesion. Nature 307:468\u2013471","journal-title":"Nature"},{"key":"71_CR33","doi-asserted-by":"publisher","first-page":"e37558","DOI":"10.7554\/eLife.37558","volume":"7","author":"D Matthies","year":"2018","unstructured":"Matthies D, Bae C, Toombes GE, Fox T, Bartesaghi A, Subramaniam S, Swartz KJ (2018) Single-particle cryo-EM structure of a voltage-activated potassium channel in lipid nanodiscs. Elife 7:e37558. https:\/\/doi.org\/10.7554\/eLife.37558","journal-title":"Elife"},{"key":"71_CR34","doi-asserted-by":"publisher","first-page":"14734","DOI":"10.1021\/bi026546a","volume":"41","author":"RE Middleton","year":"2002","unstructured":"Middleton RE, Warren VA, Kraus RL, Hwang JC, Liu CJ, Dai G, Brochu RM, Kohler MG, Gao YD, Garsky VM, Bogusky MJ, Mehl JT, Cohen CJ, Smith MM (2002) Two tarantula peptides inhibit activation of multiple sodium channels. Biochemistry 41:14734\u201314747. https:\/\/doi.org\/10.1021\/bi026546a","journal-title":"Biochemistry"},{"key":"71_CR35","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/0896-6273(95)90057-8","volume":"15","author":"C Miller","year":"1995","unstructured":"Miller C (1995) The charybdotoxin family of K+-channel-blocking peptides. Neuron 15:5\u201310","journal-title":"Neuron"},{"key":"71_CR36","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1042\/BJ20041379","volume":"385","author":"S Mouhat","year":"2005","unstructured":"Mouhat S, Visan V, Ananthakrishnan S, Wulff H, Andreotti N, Grissmer S, Darbon H, De Waard M, Sabatier JM (2005) K+ channel types targeted by synthetic OSK1, a toxin from Orthochirus scrobiculosus scorpion venom. Biochem J 385:95\u2013104","journal-title":"Biochem J"},{"key":"71_CR37","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1038\/d41573-019-00014-x","volume":"18","author":"A Mullard","year":"2019","unstructured":"Mullard A (2019) 2018 FDA drug approvals. Nat Rev Drug Discov 18:85\u201389. https:\/\/doi.org\/10.1038\/d41573-019-00014-x","journal-title":"Nat Rev Drug Discov"},{"key":"71_CR38","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1002\/glia.23078","volume":"65","author":"HM Nguyen","year":"2017","unstructured":"Nguyen HM, Grossinger EM, Horiuchi M, Davis KW, Jin LW, Maezawa I, Wulff H (2017) Differential Kv1.3, KCa3.1, and Kir2.1 expression in \u201cclassically\u201d and \u201calternatively\u201d activated microglia. Glia 65:106\u2013121. https:\/\/doi.org\/10.1002\/glia.23078","journal-title":"Glia"},{"key":"71_CR39","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1016\/j.neuropharm.2017.07.002","volume":"127","author":"RS Norton","year":"2017","unstructured":"Norton RS, Chandy KG (2017) Venom-derived peptide inhibitors of voltage-gated potassium channels. Neuropharmacology 127:124\u2013138. https:\/\/doi.org\/10.1016\/j.neuropharm.2017.07.002","journal-title":"Neuropharmacology"},{"key":"71_CR40","doi-asserted-by":"publisher","first-page":"4690","DOI":"10.1039\/c6cs00076b","volume":"45","author":"B Oller-Salvia","year":"2016","unstructured":"Oller-Salvia B, Sanchez-Navarro M, Giralt E, Teixido M (2016) Blood-brain barrier shuttle peptides: an emerging paradigm for brain delivery. Chem Soc Rev 45:4690\u20134707. https:\/\/doi.org\/10.1039\/c6cs00076b","journal-title":"Chem Soc Rev"},{"key":"71_CR41","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1177\/2040622313485275","volume":"4","author":"K Orlicka","year":"2013","unstructured":"Orlicka K, Barnes E, Culver EL (2013) Prevention of infection caused by immunosuppressive drugs in gastroenterology. Ther Adv Chronic Dis 4:167\u2013185. https:\/\/doi.org\/10.1177\/2040622313485275","journal-title":"Ther Adv Chronic Dis"},{"key":"71_CR43","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1016\/j.it.2004.09.002","volume":"25","author":"G Panyi","year":"2004","unstructured":"Panyi G, Vamosi G, Bodnar A, Gaspar R Jr, Damjanovich S (2004a) Looking through ion channels: recharged concepts in T cell signaling. Trends Immunol 25:565\u2013569","journal-title":"Trends Immunol"},{"key":"71_CR44","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.imlet.2003.11.020","volume":"92","author":"G Panyi","year":"2004","unstructured":"Panyi G, Varga Z, Gaspar R (2004b) Ion channels and lymphocyte activation. Immunol Lett 92:55\u201366","journal-title":"Immunol Lett"},{"key":"71_CR42","doi-asserted-by":"publisher","first-page":"2199","DOI":"10.2174\/138161206777585120","volume":"12","author":"G Panyi","year":"2006","unstructured":"Panyi G, Possani LD, Rodriguez de la Vega RC, Gaspar R, Varga Z (2006) K+ channel blockers: novel tools to inhibit T cell activation leading to specific immunosuppression. Curr Pharm Des 12:2199\u20132220","journal-title":"Curr Pharm Des"},{"key":"71_CR45","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1124\/mol.108.052704","volume":"75","author":"MW Pennington","year":"2009","unstructured":"Pennington MW, Beeton C, Galea CA, Smith BJ, Chi V, Monaghan KP, Garcia A, Rangaraju S, Giuffrida A, Plank D, Crossley G, Nugent D, Khaytin I, Lefievre Y, Peshenko I, Dixon C, Chauhan S, Orzel A, Inoue T, Hu X, Moore RV, Norton RS, Chandy KG (2009) Engineering a stable and selective peptide blocker of the Kv1.3 channel in T lymphocytes. Mol Pharmacol 75:762\u2013773","journal-title":"Mol Pharmacol"},{"key":"71_CR46","doi-asserted-by":"publisher","first-page":"797","DOI":"10.3233\/JAD-141704","volume":"44","author":"S Rangaraju","year":"2015","unstructured":"Rangaraju S, Gearing M, Jin LW, Levey A (2015) Potassium channel Kv1.3 is highly expressed by microglia in human Alzheimer\u2019s disease. J Alzheimers Dis 44:797\u2013808. https:\/\/doi.org\/10.3233\/JAD-141704","journal-title":"J Alzheimers Dis"},{"key":"71_CR47","doi-asserted-by":"publisher","first-page":"4509","DOI":"10.1038\/srep04509","volume":"4","author":"MH Rashid","year":"2014","unstructured":"Rashid MH, Huq R, Tanner MR, Chhabra S, Khoo KK, Estrada R, Dhawan V, Chauhan S, Pennington MW, Beeton C, Kuyucak S, Norton RS (2014) A potent and Kv1.3-selective analogue of the scorpion toxin HsTX1 as a potential therapeutic for autoimmune diseases. Sci Rep 4:4509. https:\/\/doi.org\/10.1038\/srep04509","journal-title":"Sci Rep"},{"key":"71_CR48","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1016\/j.toxicon.2004.03.022","volume":"43","author":"RC Rodriguez de la Vega","year":"2004","unstructured":"Rodriguez de la Vega RC, Possani LD (2004) Current views on scorpion toxins specific for K+-channels. Toxicon 43:865\u2013875","journal-title":"Toxicon"},{"key":"71_CR49","doi-asserted-by":"publisher","first-page":"1847","DOI":"10.1021\/acs.accounts.7b00204","volume":"50","author":"M Sanchez-Navarro","year":"2017","unstructured":"Sanchez-Navarro M, Teixido M, Giralt E (2017) Jumping hurdles: peptides able to overcome biological barriers. Acc Chem Res 50:1847\u20131854. https:\/\/doi.org\/10.1021\/acs.accounts.7b00204","journal-title":"Acc Chem Res"},{"key":"71_CR50","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1016\/0167-5699(92)90111-J","volume":"13","author":"SL Schreiber","year":"1992","unstructured":"Schreiber SL, Crabtree GR (1992) The mechanism of action of cyclosporin A and FK506. Immunol Today 13:136\u2013142. https:\/\/doi.org\/10.1016\/0167-5699(92)90111-J","journal-title":"Immunol Today"},{"key":"71_CR51","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1016\/j.bcp.2019.03.016","volume":"165","author":"A Serrano-Albarras","year":"2019","unstructured":"Serrano-Albarras A, Cirera-Rocosa S, Sastre D, Estadella I, Felipe A (2019) Fighting rheumatoid arthritis: Kv1.3 as a therapeutic target. Biochem Pharmacol 165:214\u2013220. https:\/\/doi.org\/10.1016\/j.bcp.2019.03.016","journal-title":"Biochem Pharmacol"},{"key":"71_CR52","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1038\/nrd.2016.85","volume":"15","author":"K Smietana","year":"2016","unstructured":"Smietana K, Siatkowski M, Moller M (2016) Trends in clinical success rates. Nat Rev Drug Discov 15:379\u2013380. https:\/\/doi.org\/10.1038\/nrd.2016.85","journal-title":"Nat Rev Drug Discov"},{"key":"71_CR53","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/j.ceca.2018.07.005","volume":"74","author":"KA Stauderman","year":"2018","unstructured":"Stauderman KA (2018) CRAC channels as targets for drug discovery and development. Cell Calcium 74:147\u2013159. https:\/\/doi.org\/10.1016\/j.ceca.2018.07.005","journal-title":"Cell Calcium"},{"key":"71_CR54","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2020.114146","author":"G Tajti","year":"2020","unstructured":"Tajti G, Wai DCC, Panyi G, Norton RS (2020) The voltage-gated potassium channel KV1.3 as a therapeutic target for venom-derived peptides. Biochem Pharmacol. https:\/\/doi.org\/10.1016\/j.bcp.2020.114146","journal-title":"Biochem Pharmacol"},{"key":"71_CR55","doi-asserted-by":"publisher","first-page":"22211","DOI":"10.1073\/pnas.0910123106","volume":"106","author":"Z Takacs","year":"2009","unstructured":"Takacs Z, Toups M, Kollewe A, Johnson E, Cuello LG, Driessens G, Biancalana M, Koide A, Ponte CG, Perozo E, Gajewski TF, Suarez-Kurtz G, Koide S, Goldstein SA (2009) A designer ligand specific for Kv1.3 channels from a scorpion neurotoxin-based library. Proc Natl Acad Sci USA 106:22211\u201322216","journal-title":"Proc Natl Acad Sci USA"},{"key":"71_CR56","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.clim.2017.03.014","volume":"180","author":"MR Tanner","year":"2017","unstructured":"Tanner MR, Tajhya RB, Huq R, Gehrmann EJ, Rodarte KE, Atik MA, Norton RS, Pennington MW, Beeton C (2017) Prolonged immunomodulation in inflammatory arthritis using the selective Kv1.3 channel blocker HsTX1[R14A] and its PEGylated analog. Clin Immunol 180:45\u201357. https:\/\/doi.org\/10.1016\/j.clim.2017.03.014","journal-title":"Clin Immunol"},{"key":"71_CR57","doi-asserted-by":"publisher","first-page":"e0180762","DOI":"10.1371\/journal.pone.0180762","volume":"12","author":"EJ Tarcha","year":"2017","unstructured":"Tarcha EJ, Olsen CM, Probst P, Peckham D, Munoz-Elias EJ, Kruger JG, Iadonato SP (2017) 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. https:\/\/doi.org\/10.1371\/journal.pone.0180762","journal-title":"PLoS ONE"},{"key":"71_CR58","doi-asserted-by":"publisher","first-page":"933","DOI":"10.3389\/fonc.2019.00933","volume":"9","author":"A Teisseyre","year":"2019","unstructured":"Teisseyre A, Palko-Labuz A, Sroda-Pomianek K, Michalak K (2019) Voltage-gated potassium channel Kv1.3 as a target in therapy of cancer. Front Oncol 9:933. https:\/\/doi.org\/10.3389\/fonc.2019.00933","journal-title":"Front Oncol"},{"key":"71_CR59","doi-asserted-by":"publisher","DOI":"10.3390\/molecules24020351","author":"D Tesauro","year":"2019","unstructured":"Tesauro D, Accardo A, Diaferia C, Milano V, Guillon J, Ronga L, Rossi F (2019) Peptide-based drug-delivery systems in biotechnological applications: recent advances and perspectives. Molecules. https:\/\/doi.org\/10.3390\/molecules24020351","journal-title":"Molecules"},{"key":"71_CR61","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.imlet.2009.12.015","volume":"130","author":"Z Varga","year":"2010","unstructured":"Varga Z, Hajdu P, Panyi G (2010) Ion channels in T lymphocytes: an update on facts, mechanisms and therapeutic targeting in autoimmune diseases. Immunol Lett 130:19\u201325. https:\/\/doi.org\/10.1016\/j.imlet.2009.12.015","journal-title":"Immunol Lett"},{"key":"71_CR60","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1124\/mol.112.078006","volume":"82","author":"Z Varga","year":"2012","unstructured":"Varga Z, Gurrola-Briones G, Papp F, Rodriguez de la Vega RC, Pedraza-Alva G, Tajhya RB, Gaspar R, Cardenas L, Rosenstein Y, Beeton C, Possani LD, Panyi G (2012) Vm24, a natural immunosuppressive peptide, potently and selectively blocks Kv1.3 potassium channels of human T cells. Mol Pharmacol 82:372\u2013382. https:\/\/doi.org\/10.1124\/mol.112.078006","journal-title":"Mol Pharmacol"},{"key":"71_CR62","doi-asserted-by":"publisher","first-page":"1364","DOI":"10.1124\/mol.65.6.1364","volume":"65","author":"J Vennekamp","year":"2004","unstructured":"Vennekamp J, Wulff H, Beeton C, Calabresi PA, Grissmer S, Hansel W, Chandy KG (2004) Kv1.3-blocking 5-phenylalkoxypsoralens: a new class of immunomodulators. Mol Pharmacol 65:1364\u20131374","journal-title":"Mol Pharmacol"},{"key":"71_CR63","doi-asserted-by":"publisher","first-page":"11501","DOI":"10.1073\/pnas.1612803113","volume":"113","author":"RE Wang","year":"2016","unstructured":"Wang RE, Wang Y, Zhang Y, Gabrelow C, Zhang Y, Chi V, Fu Q, Luo X, Wang D, Joseph S, Johnson K, Chatterjee AK, Wright TM, Nguyen-Tran VT, Teijaro J, Theofilopoulos AN, Schultz PG, Wang F (2016) Rational design of a Kv1.3 channel-blocking antibody as a selective immunosuppressant. Proc Natl Acad Sci USA 113:11501\u201311506. https:\/\/doi.org\/10.1073\/pnas.1612803113","journal-title":"Proc Natl Acad Sci USA"},{"key":"71_CR64","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.molcel.2020.10.039","volume":"81","author":"G Wisedchaisri","year":"2021","unstructured":"Wisedchaisri G, Tonggu L, El-Din TMG, McCord E, Zeng N, Catterall WA (2021) Structural basis for high-affinity trapping of the NaV1.7 channel in its resting state by tarantula toxin. Mol Cell 81:1\u201311. https:\/\/doi.org\/10.1016\/j.molcel.2020.10.039","journal-title":"Mol Cell"},{"key":"71_CR65","doi-asserted-by":"publisher","first-page":"1703","DOI":"10.1172\/JCI16921","volume":"111","author":"H Wulff","year":"2003","unstructured":"Wulff H, Calabresi PA, Allie R, Yun S, Pennington M, Beeton C, Chandy KG (2003) The voltage-gated Kv1.3 K+ channel in effector memory T cells as new target for MS. J Clin Invest 111:1703\u20131713","journal-title":"J Clin Invest"},{"key":"71_CR66","doi-asserted-by":"publisher","first-page":"982","DOI":"10.1038\/nrd2983","volume":"8","author":"H Wulff","year":"2009","unstructured":"Wulff H, Castle NA, Pardo LA (2009) Voltage-gated potassium channels as therapeutic targets. Nat Rev Drug Discov 8:982\u20131001. https:\/\/doi.org\/10.1038\/nrd2983","journal-title":"Nat Rev Drug Discov"},{"key":"71_CR67","doi-asserted-by":"publisher","first-page":"E7013","DOI":"10.1073\/pnas.1514728112","volume":"112","author":"R Zhao","year":"2015","unstructured":"Zhao R, Dai H, Mendelman N, Cuello LG, Chill JH, Goldstein SA (2015) Designer and natural peptide toxin blockers of the KcsA potassium channel identified by phage display. Proc Natl Acad Sci USA 112:E7013-7021. https:\/\/doi.org\/10.1073\/pnas.1514728112","journal-title":"Proc Natl Acad Sci USA"},{"key":"71_CR68","doi-asserted-by":"publisher","first-page":"E11847","DOI":"10.1073\/pnas.1816189115","volume":"115","author":"R Zhao","year":"2018","unstructured":"Zhao R, Kennedy K, De Blas GA, Orta G, Pavarotti MA, Arias RJ, de la Vega-Beltran JL, Li Q, Dai H, Perozo E, Mayorga LS, Darszon A, Goldstein SAN (2018) Role of human Hv1 channels in sperm capacitation and white blood cell respiratory burst established by a designed peptide inhibitor. Proc Natl Acad Sci USA 115:E11847\u2013E11856. https:\/\/doi.org\/10.1073\/pnas.1816189115","journal-title":"Proc Natl Acad Sci USA"}],"container-title":["Biologia Futura"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s42977-021-00071-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s42977-021-00071-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s42977-021-00071-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T14:04:26Z","timestamp":1615557866000},"score":1,"resource":{"primary":{"URL":"http:\/\/link.springer.com\/10.1007\/s42977-021-00071-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,6]]},"references-count":68,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,3]]}},"alternative-id":["71"],"URL":"https:\/\/doi.org\/10.1007\/s42977-021-00071-7","relation":{},"ISSN":["2676-8615","2676-8607"],"issn-type":[{"value":"2676-8615","type":"print"},{"value":"2676-8607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,6]]},"assertion":[{"value":"20 November 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 January 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 February 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliances with ethical standards"}},{"value":"The authors have no relevant financial or non-financial interests to disclose.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Not applicable, our paper does not contain any experiments connected to humans or animals.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}]}}