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(12) United States Patent (10) Patent No.: US 9,062,119 B2 Varga Et Al

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(12) United States Patent (10) Patent No.: US 9,062,119 B2 Varga Et Al USOO90621-19B2 (12) United States Patent (10) Patent No.: US 9,062,119 B2 Varga et al. (45) Date of Patent: Jun. 23, 2015 (54) MODIFIED PEPTIDE TOXINS OTHER PUBLICATIONS (71) Applicants:Zoltan Varga, Debrecen (HU); Gyorgy Bagdanyi, M. et al. Anuroctoxin, a new scorpion toxin of the alpha Panyi, Debrecen (HU); Gabor Toth, KTX 6 subfamily, is highly selective for Kv1.3 over IKCal ion Szeged (HU); Kinga Rakosi, Szeged channels of human T lymphocytes. Mol Pharmacol (2005), vol. 67. (HU) pp. 1034-1044. Batista, CV. et al. Two novel toxins from the Amazonian scorpion (72) Inventors: Zoltan Varga, Debrecen (HU); Gyorgy Tityus cambridgei that block Kv1.3 and Shaker BK(+)-channels with Panyi, Debrecen (HU); Gabor Toth, distinctly different affinities. Biochim Biophys Acta (2002), vol. Szeged (HU); Kinga Rakosi, Szeged 1601, pp. 123-131. Beeton, C. et al. Selective blockade of T lymphocyte K+ channels (HU) ameliorates experimental autoimmune encephalomyelitis, a model (73) Assignees: University of Debrecen, Debrecen for multiple sclerosis. Proc Natl Acad Sci USA (2001), vol. 98, pp. (HU); University of Szeged, Szeged 13942-13947. Beeton, C. et al. Kv1.3 channels are a therapeutic target for T cell (HU) mediated autoimmune diseases. Proc Natl AcadSci USA (2006), vol. 103, pp. 17414-17419. (*) Notice: Subject to any disclaimer, the term of this Corzo, G. et al. A selective blocker of Kv1.2 and Kv1.3 potassium patent is extended or adjusted under 35 channels from the venom of the Scorpion Centruroides suffusus suf U.S.C. 154(b) by 0 days. fusus. Biochem Pharmacol (2008), vol. 76, pp. 1142-1154. Dauplais, M. et al. On the convergent evolution of animal toxins. Conservation of a diad of functional residues in potassium channel (21) Appl. No.: 14/354,540 blocking toxins with unrelated structures. J Biol Chem (1997), vol. 272, pp. 4302-4309. Goldstein, SA. etal. Mechanism of charybdotoxin block of a voltage (22) PCT Filed: Oct. 29, 2012 gated K+ channel. Biophys J (1993), vol. 65, pp. 1613-1619. Han, S. etal. Structural Basis of a Potent Peptide Inhibitor Designed (86). PCT No.: PCT/HU2012/000117 for Kv1.3 Channel, a Therapeutic Target of Autoimmune Disease. J Biol Chem (2008), vol. 28.3(27), pp. 19058-19065. S371 (c)(1), Jouirou, B. et al. Cobatoxin 1 from Centruroides noxius scorpion venom: chemical synthesis, three-dimensional structure in Solution, (2) Date: Apr. 25, 2014 pharmacology and docking on K+ channels. Biochem J. (2004), vol. 377, pp. 37-49. (87) PCT Pub. No.: WO2013/061106 Leonard, R.J. et al. Selective blockers of voltage-gated K+ channels depolarize human T lymphocytes: mechanism of the antiproliferative PCT Pub. Date: May 2, 2013 effect of charybdotoxin. Proc Natl AcadSci USA (1992), vol. 89, pp. 10094-10098. M'Barek, S. et al. Synthesis and characterization of Pi4, a scorpion (65) Prior Publication Data toxin from Pandinus imperator that acts on K+ channels. Eur J Biochem (2003), vol. 270, pp. 3583-3592. US 2015/OO876O3 A1 Mar. 26, 2015 Mouhat, S. et al. The functional dyad of scorpion toxin Pil is not itself a prerequisite for toxin binding to the voltage-gated Kv1.2 (30) Foreign Application Priority Data potassium channels. Biochem J. (2004), vol. 377, pp. 25-36. Panyi, G. et al. K+ channel blockers: novel tools to inhibit T cell activation leading to specific immunosuppression. Curr Pharm Des Oct. 28, 2011 (HU) ...................................... 1100604 (2006), vol. 12, pp. 2199-2220. Panyi, G. et al. Ion channels and lymphocyte activation. Immunol Lett (2004), vol. 92, pp.55-66. (51) Int. Cl. Papp, F. et al. Tst26, a novel peptide blocker of Kv1.2 and Kv1.3 A6 IK38/00 (2006.01) channels from the venom of Tityus stigmurus. Toxicon (2009), vol. A6 IK38/28 (2006.01) 54, pp. 379-389. Pennington, MW. et al. Engineering a stable and selective peptide A6IP3/10 (2006.01) blocker of the Kv1.3 channel in T lymphocytes. Mol Pharmacol A6IP 7/2 (2006.01) (2009), vol. 75, pp. 762-773. A6IP 9/02 (2006.01) Peter, M. etal. Blockage of human T lymphocyte Kv1.3 channels by A6IP 29/00 (2006.01) Pil, a novel class of scorpion toxin. Biochem Biophys Res Commun (2000), vol. 278, pp. 34-37. C07K I4/47 (2006.01) Peter, M. etal. Effects of toxins Pi2 and Pi3 on human T lymphocyte A6 IK38/6 (2006.01) Kv1.3 channels: the role of Glu7 and Lys24. J Membrane Biol C07K I4/435 (2006.01) (2001), vol. 179, pp. 13-25. Pimentel, C. et al. Chemical synthesis and 1H-NMR 3D structure (52) U.S. Cl. determination of AgTx2-MTX chimera, a new potential blocker for CPC ................................ C07K 14/43522 (2013.01) Kv1.2 channel, derived from MTX and AgTx2 scorpion toxins. Pro (58) Field of Classification Search tein Sci (2008), vol. 17, pp. 107-118. None (Continued) See application file for complete search history. Primary Examiner — Marcela M Cordero Garcia Assistant Examiner — Sergio Coffa (56) References Cited (74) Attorney, Agent, or Firm — Seth D. Levy; Nixon U.S. PATENT DOCUMENTS Peabody LLP (57) ABSTRACT 6,861.405 B2 3/2005 Desir et al. The invention relates to toxin peptides capable of selectively 2007/007 1764 A1 3/2007 Sullivan et al. inhibiting a Kv1.3 potassium channel protein. The toxin pep tides of the invention are modified anuroctonus Scorpion FOREIGN PATENT DOCUMENTS toxin peptides. WO 2006002850 A2 1, 2006 22 Claims, 5 Drawing Sheets US 9,062,119 B2 Page 2 (56) References Cited Varga, Z. etal. Vm24, a natural immunosuppressive peptide, potently and selectively blocks Kv1.3 potassium channels of human T cells. Mol Pharmacol (2012), vol. 82(3), pp. 372-382. OTHER PUBLICATIONS Visan, V. et al. Mapping of maurotoxin binding sites on hKv1.2, Srinivasan, KN. et al. kappa-Hefutoxin1, a novel toxin from the hKv1.3, and hIKCal channels. Mol Pharmacol (2004), vol. 66, pp. Scorpion Heterometrus filvipes with unique structure and function: 1103-1112. Importance of the functional diad in potassium channel selectivity. J Wulff. H. et al. The voltage-gated Kv1.3 K+ channel in effector Biol Chem (2002), vol. 277, pp. 30040-30047. memory T cells as new target for MS. J. Clin Invest (2003), vol. 111, Tucker, K. et al. Kv1.3 gene-targeted deletion alters longevity and pp. 1703-1713. reduces adiposity by increasing locomotion and metabolism in Yin, S.J. et al. Different Residues in Channel Turret Determining the melanocortin-4 receptor-null mice. International Journal of Obesity Selectivity of ADWX-1 Inhibitor Peptide between Kv1.1 and Kv1.3 (2008), pp. 1-11. Channels. J Prot Res (2008), vol. 7(11), pp. 4890-4897. U.S. Patent Jun. 23, 2015 Sheet 1 of 5 US 9,062,119 B2 1.0 - - - - ...N. '...N. 0.8 - '. 0.6 0.4 e WT e K16D,F32T 0.2 v N17AF32T ''. A F32T “b. Ya . O.O sia. -- 0.01 0.1 1 10 toxin concentration (nM) FIGURE 1 0.0.0.O.1. 24.68O 0. O WT FIGURE 2 U.S. Patent Jun. 23, 2015 Sheet 2 of 5 US 9,062,119 B2 y Ne 9 N Y 0.8 *. W . K16D,N17A,F32Y ". Y -- AAA, K16D,N17A.F32T E V \ . K16D,N17AF32T 0.6 s y hs N t V s 0.4 V V N Es '. y y W 0.2 - t Y 1. ''. N N a.... N 0.0 - - - - - - - - - -----Ti, 0.1 1 10 100 1000 1OOOO toxin concentration (nM) FIGURE 3 U.S. Patent Jun. 23, 2015 Sheet 3 of 5 US 9,062,119 B2 dyad external vestibule water filled cavity FIGURE 4 U.S. Patent Jun. 23, 2015 Sheet 4 of 5 US 9,062,119 B2 N-terminus C-terminus FIGURES U.S. Patent Jun. 23, 2015 Sheet 5 of 5 US 9,062,119 B2 FIGURE 6 FIGURE 7 NMR structure of synthetic AnTx and its N17A, F32Tmutant (side view 2) US 9,062,119 B2 1. 2 MODIFIED PEPTIDE TOXINS It is especially important that effector memory T cells (CCR7CD45RA), which are major contributors to the CROSS-REFERENCE TO RELATED pathogenesis of several autoimmune diseases (multiple scle APPLICATIONS rosis, type I diabetes) express Kv1.3 channels in much higher numbers than naive (CCR7CD45RA) and central memory This application is a National Phase of International Appli (CCR7"CD45RA) T cells and consequently their prolifera cation No. PCT/HU2012/000117, filed Oct. 29, 2012, which tion relies acutely on the operation of these channels. Thus, designated the U.S. and that International Application was the progression of certain autoimmune diseases may be con published under PCT Article 21(2) in English. This applica trolled with Kv1.3 blockers of high affinity and specificity, tion also includes a claim of priority under 35 U.S.C. S 119(a) 10 and these compounds could serve as the basis for the devel and S365(b) to Hungarian patent application No. P1 100604, opment of drugs for the treatment of autoimmune diseases in filed Oct. 28, 2011. the future. Using Such a high affinity potassium channel The invention relates to toxin peptides capable of selec blocking toxin the symptoms of experimental autoimmune tively inhibiting a Kv1.3 potassium channel protein. The encephalomyelitis (EAE), which serves as a model of mul toxin peptides of the invention are modified anuroctonus 15 tiple Sclerosis could be ameliorated in experimental animals Scorpion toxin peptides. (Becton et al., 2001b). This is of great importance because Ion Channels as Potential Targets in the Treatment of today many drugs exist that act by affecting ion channels in Autoimmune Diseases various cells (especially muscle cells and neurons), but the During the course of an autoimmune disease the immune manipulation of the cells of the immune system via ion chan system attacks the organism's own cells and tissues, such as nels is still a practically untouched area holding great poten the insulin producing cells in type I diabetes or the insulating tial.
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