Calcium Channel Blocking Polypeptides

Structure, Function, and Molecular Mimicry
  • Raymond S. Norton
  • Jonathan B. Baell
  • James A. Angus


Venomous creatures produce a wealth of interesting peptide and protein toxins as components of their venoms. Many such peptide and protein toxins are potent and highly selective blockers or modulators of calcium channel function, and as such are valuable pharmacological tools and potentially valuable leads in human therapeutic development. Cone shells and spiders are rich sources of such toxins, although they are also found in scorpions and insects. In this chapter we compare the amino acid sequences of toxins active against calcium channels and describe their three dimensional structures and structure-function relationships. Certain structural motifs, in particular the inhibitor cystine knot, prove to be quite common amongst this class of toxins. Aspects of the pharmacology and physiology of these toxins in mammalian systems are discussed, with an emphasis on their application to the treatment of chronic pain. We then consider how these naturally occurring toxins might be mimicked in non-peptide (peptidomimetic) compounds that could be useful therapeutically for the treatment of pain and in other indications.


Calcium Channel Neuropathic Pain Scorpion Toxin Conscious Rabbit Spider Toxin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Adams, D. J., Smith, A. B., Schroeder, C. I., Yasuda T., Lewis R. J., 2003, ω-conotoxin CVID inhibits a phannacologically distinct voltage-sensitive calcium channel associated with transmitter release from preganglionic nerve terminals, J Biol Chem 278:4057–4062.PubMedGoogle Scholar
  2. Adams, M. E., Bindokas, V. P., Hasegawa, L. and Venema, V. J., 1990, ω-Agatoxins: novel calcium channel antagonists of two subtypes from funnel web spider (Agelenopsis aperta) venom, J Biol Chem 265:861–867.PubMedGoogle Scholar
  3. Adams, M. E., Mintz, I. M., Reily, M. D., Thanabal, V. and Bean, B. P., 1993, Structure and properties of ω-agatoxin IVB, a new antagonist of P-type calcium channels, Mol Pharmacol 44:681–688.PubMedGoogle Scholar
  4. Asakura, K., Kanemasa, T., Minagawa, K., Kagawa, K. and Ninomiya, M., 1999, The nonpeptide alpha-eudexp61 from Juniperus virginiana Linn. (Cupressaceae) inhibits ω-agatoxin IVA-sensitive Ca2+ currents and synaptosomal 45Ca2+ uptake, Brain Res 823:169–176.PubMedGoogle Scholar
  5. Atanassoff, P. G., Hartmannsgruber, M. W., Thrasher, J., Wermeling, D., Longton, W., Gaeta, R., Singh, T., Mayo, M., McGuire, D. and Luther, R. R., 2000, Ziconotide, a new N-type calcium channel blocker, administered intrathecally for acute postoperative pain, Reg Anesth PainMed 25:274–278.Google Scholar
  6. Atkinson RA, Kieffer B, Dejaegere A, Sirockin F, and Lefevre JF, 2000, Structural and dynamic characterization of ω-conotoxin MVIIA: the binding loop exhibits slow conformational exchange, Biochemistry 39:3908–19.PubMedGoogle Scholar
  7. Baell. J, B., Forsyth, S. A, Gable, R. W., Norton, R. S. and Mulder, R. J., 2001, Design and synthesis of type-III mimetics of ω-conotoxin GVIA, J Comput Aided Mol Des 15:1119–1136.PubMedGoogle Scholar
  8. Baell, J. B., Harvey, A. J. and Norton, R. S., 2002, Design and synthesis of type-III mimetics of ShK toxin, J Comput Aided Mol Des 16:245–262.PubMedGoogle Scholar
  9. Balaji, R. A, Ohtake, A., Sato, K., Gopalakrishnakone, P., Kini, R. M., Seow, K. T. and Bay, B. H., 2000, λ-conotoxins, a new family of conotoxins with unique disulfide pattern and protein folding. Isolation and characterization from the venom of Conus marmoreus, J Biol Chem 275:39516–39522.PubMedGoogle Scholar
  10. Ball, J. B. and Alewood, P. F., 1990, Conformational constraints: nonpeptide beta-turn mimics, J Mol Recognit 3:55–64.PubMedGoogle Scholar
  11. Basus, V. J., Nadasdi, L., Ramachandran, J. and Miljanich, G. P., 1995, Solution structure of ω-conotoxin MVIIA using 2D NMR spectroscopy, FEBS Lett 370:163–169.PubMedGoogle Scholar
  12. Bernard, C., Corzo, G., Mosbah, A., Nakajima, T. and Darbon, H., 2001, Solution structure of Ptul, a toxin from the assassin bug Peirates turpis that blocks the voltage-sensitive calcium channel N-type, Biochemistry 40:12795–12800.PubMedGoogle Scholar
  13. Bindokas, V. P. and Adams, M. E., 1989, ω-Aga-I: a presynaptic calcium channel antagonist from venom of the funnel web spider, Agelenopsis aperta, J Neurobiol 20:171–188.PubMedGoogle Scholar
  14. Bindokas, V. P., Venema, V. J. and Adams, M. E., 1991, Differential antagonism of transmitter release by subtypes of ω-agatoxins, J Neurophysiol 66:590–601.PubMedGoogle Scholar
  15. Blaber, M., Baase, W. A, Gassner, N. and Matthews, B. W., 1995, Alanine scanning mutagenesis of the α-helix 115-123 of phage T4 lysozyme: effects on structure, stability and the binding of solvent, J Mol Biol 246:317–330.PubMedGoogle Scholar
  16. Bodor, N., and Buchwald, P., 2002, Barriers to remember: brain-targeting chemical delivery systems and Alzheimer’s disease, Drug Discov Today 7:766–774.PubMedGoogle Scholar
  17. Bogan, A. A. and Thorn, K.S., 1998, Anatomy of hot spots in protein interfaces, J Mol Biol 280:1–9.PubMedGoogle Scholar
  18. Boigegrain, R. A, Mattras, H., Brehelin, M., Paroutaud, P. and Coletti-Previero, M. A, 1992, Insect immunity: two proteinase inhibitors from hemolymph of Locusta migratorio, Biochem Biophys Res Commun 189:790–793.PubMedGoogle Scholar
  19. Bowersox, S. S., Singh, T., and Luther, R. R., 1997, Selective blockade of N-type voltage-sensitive calcium channels protects against brain injury after transient focal cerebral ischemiain rats, Brain Res 747:343–347.PubMedGoogle Scholar
  20. Branton, W. D., Rudnick, M. S., Zhou, Y., Eccleston, E. D., Fields, O. B. and Bowers, L. D., 1993, Fatty acylated toxin structure, Nature 365:496–497.PubMedGoogle Scholar
  21. Brose, W. G., Gutlove, D. P., Luther, R. R., Bowersox, S. S., and McGuire, D., 1997, Use of intrathecal SNX-111, a novel, N-type, voltage-sensitive, calcium channel blocker, in the management of intractable brachial plexus avulsion pain, Clin J Pain 13:256–259.PubMedGoogle Scholar
  22. Burgess, K., 2001, Solid-phase syntheses of β-turn analogues to mimic or disrupt protein-protein interactions, Acc Chem Res 34:826–835.PubMedGoogle Scholar
  23. Bums, L. H., Jin, Z. and Bowersox, S. S., 1999, The neuroprotective effects of intrathecal administration of the selective N-type calcium channel blocker ziconotide in a rat model of spinal ischemia, J Vase Surg 30:334–343.Google Scholar
  24. Cassola, A. C., Jaffe, H., Fales, H. M., Castro Meche, S., Magnoli, F. and Cipolla-Neto, J., 1998, ω-phonetoxin-IIA: a calcium channel blocker from the spider Phoneutria nigriventer, Pflugers Arch 436:545–552.PubMedGoogle Scholar
  25. Chen, L., Tilley, J., Trilles, R. V., Yun, W., Fry, D., Cook, C., Rowan, K., Schwinge, V. and Campbell, R., 2002, N-acyl-L-phenylalanine derivatives as potent VLA-4 antagonists that mimic a cyclic peptide conformation, Bioorg Med Chem Lett 12:137–140.PubMedGoogle Scholar
  26. Chuang, R. S., Jaffe, H., Cribbs, L., Perez-Reyes, E. and Swartz, K. J., 1998, Inhibition of T-type voltage-gated calcium channels by a new scorpion toxin, Nat Neurosci 1:668–674.PubMedGoogle Scholar
  27. Civera, C., Vazquez, A., Sevilla, J. M., Bruix, M., Gago, F., Garcia, A. G. and Sevilla, P., 1999, Solution structure determination by two-dimensional 1H NMR of ω-conotoxin MVIID, a calcium channel blocker peptide, Biochem Biophys Res Commun 254:32–35.PubMedGoogle Scholar
  28. Clackson, T. and Wells, J. A., 1995, A hot spot of binding energy in a hormone-receptor interface, Science 267:383–6.PubMedGoogle Scholar
  29. Cordeiro Mdo, N., de Figueiredo, S. G., Valentim Ado, C., Diniz, C. R., von Eickstedt, V. R., Gilroy, J. and Richardson, M., 1993, Purification and amino acid sequences of six Tx3 type neurotoxins from the venom of the Brazilian ‘armed’ spider Phoneutria nigriventer, Toxicon 31:35–42.Google Scholar
  30. Corzo, G., Adachi-Akahane, S., Nagao, T., Kusui, Y. and Nakajima, T., 2001, Novel peptides from assassin bugs (Hemiptera: Reduviidae): isolation, chemical and biological characterization, FEBS Lett 499:256–261.PubMedGoogle Scholar
  31. Cousins, M. J., Goucke, C., Cher, L. M., Brooker, C. D., Amor, P. E., and Crump, D. E., Aphase 1 clinicaltrial of AM336, a novel N-type calcium channel blocker. In, Abstracts of 10 th World Congress on Pain, August 17–22, 2002, San Diego, CA, USA, IASP Press, Seattle, p. 201.Google Scholar
  32. Dauplais, M., Lecoq, A, Song, J., Cotton, J., Jamin, N., Gilquin, B., Roumestand, C., Vita, C., de Medeiros, C. L., Rowan, E. G., Harvey, A L. and Menez, A., 1997, On the convergent evolution of animal toxins. Conservation of a diad of functional residues in potassium channel-blocking toxins with unrelated structures, J Biol Chem 272:4302–4309.PubMedGoogle Scholar
  33. Davis, J. H., Bradley, E. K., Miljanich, G. P., Nadasdi, L., Ramacbandran, J. and Basus, V. J., 1993, Solution structure of ω-conotoxin GVIA using 2-D NMR spectroscopy and relaxation matrix analysis, Biochemistry 32:7396–7405.PubMedGoogle Scholar
  34. de los Rios, C., Marco, J. L., Carreiras, M. D., Chinchon, P. M., Garcia, A. G. and Villarroya, M., 2002, Novel tacrine derivatives that block neuronal calcium channels, Bioorg Med Chem 10:2077–2088.PubMedGoogle Scholar
  35. de Weille, J. R., Schweitz, H., Maes, P., Tartar, A and Lazdunski, M., 1991, Calciseptine, a peptide isolated from black mamba venom, is a specific blocker of the L-type calcium channel, Proc Natl Acad Sci USA 88:2437–2440.PubMedGoogle Scholar
  36. Diniz, C. R., Cordeiro Mdo, N., Junor, L. R., Kelly, P., Fischer, S., Reimann, F., Oliveira, E. B. and Richardson, M., 1990, The purification and amino acid sequence of the lethal neurotoxin Tx1 from the venom of the Brazilian ‘armed’ spider Phoneutria nigriventer, FEBS Lett 263:251–253.PubMedGoogle Scholar
  37. Dooley, D. J., Donovan, C. M., Meder, W. P. and Whetzel, S. Z., 2002, Preferential action of gabapentin and pregabalin at P/Q-type voltage-sensitive calcium channels: inhibition of K+-evoked [3H]-norepinephrine release from rat neocortical slices, Synapse 45:171–190.PubMedGoogle Scholar
  38. Dos Santos, R. G., Van Renterghem, C., Martin-Moutot, N., Mansuelle, P., Cordeiro, M. N., Diniz, C. R., Mori, Y., De Lima, M. E. and Seagar, M., 2002, Phoneutria nigriventer ω-phonetoxin IIA blocks the Cav2 family of calcium channels and interacts with ω-conotoxin-binding sites, J Biol Chem 277:13856–13862.PubMedGoogle Scholar
  39. Doughty, S. W., Blaney, F. E., Orlek, B. S. and Richards, W. G., 1998, A molecular mechanism for toxin block in N-type calcium channels, Protein Eng 11:95–99.PubMedGoogle Scholar
  40. Doughty, S. W., Blaney, F. E. and Richards, W. G., 1995, Models of ion pores in N-type voltage-gated calcium channels, J Mol Graph 13:342–348.PubMedGoogle Scholar
  41. Ellinor, P. T., Zhang, J. F., Home, W. A. and Tsien, R. W., 1994, Structural determinants of the blockade of N-type calcium channels by a peptide neurotoxin, Nature 372:272–275.PubMedGoogle Scholar
  42. Ernst., J. T., Kutzki, O., Debnath, A. K., Jiang, S., Lu, H. and Hamilton, A. D., 2002, Design of a protein surface antagonist based on alpha-helix mimicry: inhibition of gp41 assembly and viral fusion, Angew Chem Int Ed Eng 41:278–281.Google Scholar
  43. Ertel, E. A, Warren, V. A, Adams, M. E., Griffin, P. R., Cohen, C. J. and Smith, M. M., 1994, Type III ω-agatoxins: a family of probes for similar binding sites on L-and N-type calcium channels, Biochemistry 33:5098–5108.PubMedGoogle Scholar
  44. Fajloun, Z., Kharrat, R., Chen, L., Lecomte, C., Di Luccio, E., Bichet, D., El Ayeb, M., Rochat, H., Allen, P. D., Pessah, I. N., De Waard, M. and Sabatier, J. M., 2000, Chemical synthesis and characterization of maurocalcine, a scorpion toxin that activates Ca2+ release channel/ryanodine receptors, FEBS Lett 469:179–185.PubMedGoogle Scholar
  45. Farr-Jones, S., Miljanich, G. P., Nadasdi, L., Ramachandran, J. and Basus, V. J., 1995, Solution structure of ω-conotoxin MVIIC, a high affinity ligand of P-type calcium channels, using 1H NMR spectroscopy and complete relaxation matrix analysis, J Mol Biol 248:106–124.PubMedGoogle Scholar
  46. Feng, Z. P., Hamid, J., Doering, C., Bosey, G. M., Snutch, T. P. and Zamponi, G.W., 2001, Residue Gly1326 of the N-type calcium channel α1B subunit controls reversibility of ω-conotoxin GVIA and MVIIA block, J Biol Chem 276:15728–15735.PubMedGoogle Scholar
  47. Flinn, J. P., Pallaghy, P. K., Lew, M. J., Murphy, R., Angus, J. A and Norton, R. S., 1999a, Role of disulfide bridges in the folding, structure and biological activity of ω-conotoxin GVIA, Biochim Biophys Acta 1434:177–190.PubMedGoogle Scholar
  48. Flinn, J. P., Pallaghy, P. K., Lew, M. J., Murphy, R., Angus, J. A. and Norton, R. S., 1999b, Roles of key functional groups in ω-conotoxin GVIA synthesis, structure and functional assay of selected peptide analogues, Eur J Biochem 262:447–455.PubMedGoogle Scholar
  49. Gadek, T. R., Burdick, D. J., McDowell, R. S., Stanley, M. S., Marsters, J. C., Jr., Paris, K. J., Oare, D. A, Reynolds, M. E., Ladner, C., Zioncbeck, K. A, Lee, W. P., Gribling, P., Dennis, M. S., Skehon, N. J., Tumas, D. B., Clark, K. R., Keating. S. M., Beresini, M. H., Tilley, J. W., Presta, L. G. and Bodary, S. C., 2002, Generation of an LFA-l antagonist by the transfer of the ICAM-l immunoregulatory epitope to a small molecule, Science 295:1086–1089.PubMedGoogle Scholar
  50. Gage, M. J., Rane, S. G., Hockerman, G. H. and Smith, T. J., 2002, The virally encoded fungal toxin KP4 specifically blocks L-type voltage-gated calcium channels, Mol Pharmacol 61:936–944.PubMedGoogle Scholar
  51. Garcia, E., Scanlon, M. and Naranjo, D., 1999, A marine snail neurotoxin shares with scorpion toxins a convergent mechanism of blockade on the pore of voltage-gated K channels, J Gen Physiol 114:141–157.PubMedGoogle Scholar
  52. Gasparini, S., Danse, J. M., Lecoq, A, Pinkasfeld, S., Zinn-Justin, S., Young, L. C., de Medeiros, C. C., Rowan, E. G., Harvey, A L. and Menez, A., 1998, Delineation of the functional site of α-dendrotoxin. The functional topographies of dendrotoxins are different but share a conserved core with those of other Kv1 potassium channel-blocking toxins, J Biol Chem 273:25393–25403.PubMedGoogle Scholar
  53. Gilquin, B., Lecoq, A., Desne, F., Guenneugues, M., Zinn-Justin, S. and Menez, A, 1999, Conformational and functional variability supported by the BPTI fold: solution structure of the Ca2+ channel blocker calcicludine, Proteins 34:520–532.PubMedGoogle Scholar
  54. Goldenberg, D. P., Koehn, R. E., Gilbert, D. E. and Wagner, G., 2001, Solution structure and backbone dynamics of an ω-conotoxin precursor, Protein Sci 10:538–550.PubMedGoogle Scholar
  55. Gu, F., Khimani, A., Rane, S.G., Flurkey, W. H., Bozarth, R. F. and Smith, T. J., 1995, Structure and function of a virally encoded fungal toxin from Ustilago maydis: a fungal and mammalian Ca2+ channel inhibitor, Structure 3:805–814.PubMedGoogle Scholar
  56. Guo, Z.-X., Cammidge, A. N., and Horwell, D. C., 2000. Dendroid peptide structural mimetics of ω-conotoxin MVIIA based on a 2 (1H)-quinolinone core, Tetrahedron 56:5169–5175.Google Scholar
  57. Hagiwara, K., Sakai, T., Miwa, K., Kawai, N., and Nakajima, T., 1991, Complete amino-acid sequence of a new type of neurotoxin from the venom of the spider, Age1ena opulenta, Biomed Res 11:181–186.Google Scholar
  58. Hainsworth, A. H., Stefani., A., Calabresi, P., Smith, T. W., and Leach, M. J., 2000, Sipatrigine (BW 619C89) is a neuroprotective agent and a sodium channel and calcium channel inhibitor, CNS Drug Reviews 6:111–134.Google Scholar
  59. Hann, M. M., Leach, A. R. and Harper, G., 2001, Molecular complexity and its impact on the probability of finding leads for drug discovery, J Chem Inf Comput Sci 41:856–864.PubMedGoogle Scholar
  60. Hauel, N. H., Nar, H., Priepke, H., Ries, U., Stassen, J. M. and Wienen, W., 2002, Structure-based design of novel potent nonpeptide thrombin inhibitors, J Med Chem 45:1757–1766.PubMedGoogle Scholar
  61. Hawkes, A. L., Angus, J. A.and Wright, C. E., 1995, ω-Conotoxin GVIA and prazosin, but not felodipine, cause postural hypotension in rabbits, Clin Exp Pharmacol Physiol 22:711–716.PubMedGoogle Scholar
  62. Heck, S. D., Siok, C. J., Krapcho, K. J., Kelbaugh, P. R., Thadeio, P. F., Welch, M. J., Williarns, R. D., Ganong, A. H., Kelly, M. E., Lanzetti, A. J., Gray, W. R., Phillips, D., Parks, T. N., Jackson, H., Ahlijanian, M. K., Saccomano, N. A, and Volkmann, R. A, 1994, Functional consequences of posttranslational isomerization of Ser46 in a calcium channel toxin, Science 266:1065–1068.PubMedGoogle Scholar
  63. Hill, J. M., Alewood, P. F. and Craik, D. J., 1996, Three-dimensional solution structure of µ-conotoxin GIIIB, a specific blocker of skeletal muscle sodium channels, Biochemistry 35:8824–8835.Google Scholar
  64. Hill, J. M., Alewood, P. F. and Craik, D. J., 1997, Solution structure of the sodium channel antagonist conotoxin GS: a new molecular caliper for probing sodium channel geometry, Structure 5:571–583.PubMedGoogle Scholar
  65. Hill, J. M., Alewood, P. F. and Craik, D. J., 2000, Conotoxin TVIIA, a novel peptide from the venom of Conus tulipa 2. Three-dimensional solution structure, Eur J Biochem 267:4649–4657.PubMedGoogle Scholar
  66. Hu, L. Y., Ryder, T. R., Rafferty, M. F., Siebers, K. M., Malone, T., Chatteljee, A., Feng, M. R., Lotarski, S. M., Rock, D. M., Stoehr, S. J., Taylor, C. P., Weber, M. L., Miljanich, G. P., Millerman, E. and Szoke, B. G., 2000a, Neuronal N-type calcium channel blockers: a series of 4-piperidinylaniline analogs with analgesic activity, Drug Des Discov 17:85–93.PubMedGoogle Scholar
  67. Hu, L. Y., Ryder, T. R., Rafferty, M. F., Taylor, C. P., Feng, M. R., Kuo, B. S., Lotarski, S. M., Miljanich, G. P., Millerman, E., Siebers, K. M. and Szoke, B. G., 2000b, The discovery of [1-(4-dimethylamino-benzyl) piperidin-4-yl]-[4-(3,3-dimethylbutyl)-phenyl]-(3-methyl-but-2-enyl)-amine, an N-type Ca2+ channel blocker with oral activity for analgesia, Bioorg Med Chem 8:1203–1212.PubMedGoogle Scholar
  68. Inui, T., Hagiwara, K., Nakajima, K., Kimura, T., Nakajima, T. and Sakakibara, S., 1992, Synthesis and disulfide structure determination of agelenin: identification of the carboxy-terminus as an amide form, Pept Res 5:140–144.PubMedGoogle Scholar
  69. lsaacs, N. W., 1995, Cystineknots, Curr Opin Struct Biol 5:391–395.Google Scholar
  70. Jones, R.M. and Bulaj, G., 2000, Conotoxins-new vistas for peptide therapeutics, Curr Pharm Des 6:1249–1285.PubMedGoogle Scholar
  71. Kalapothakis, E., Penaforte, C. L., Leao, R. M., Cruz, J. S., Prado, V. F., Cordeiro, M. N., Diniz, C. R., Romano-Silva, M. A, Prado, M. A, Gomez, M. V. and Beirao, P. S., 1998, Cloning, cDNA sequence analysis and patch clamp studies of a toxin from the venom of the armed spider (Phoneutria nigriventer), Toxicon 36:1971–1980.PubMedGoogle Scholar
  72. Kim, J. I., Konishi, S., Iwai, H., Koimo, T., Gouda, H., Shimada, I., Sato, K and Arata, Y., 1995a, Three dimensional solution structure of the calcium channel antagonist ω-agatoxin IVA: consensus molecular folding of calcium channel blockers, J Mol Biol 250:659-671.Google Scholar
  73. Kim, J. I., Takahashi, M., Ohtake, A., Wakarniya, A and Sato, K., 1995b, Tyrl3 is essential for the activity of ω-conotoxin MVIIA and GVIA, specific N-type calcium channel blockers, Biochem Biophys Res Commun 206:449–454.PubMedGoogle Scholar
  74. Kim, J. I., Takahashi, M., Ogura, A., Kohno, T., Kudo, Y. and Sato, K, 1994, Hydroxyl group of Tyr13 is essential for the activity of ω-conotoxin GVIA, a peptide toxin for N-type calcium channel, J Biol Chem 269:23876–23878.PubMedGoogle Scholar
  75. Kobayashi, K., Sasaki, T., Sato, K. and Kohno, T., 2000, Three-dimensional solution structure of ω-conotoxin TxVII, an L-type calcium channel blocker, Biochemistry 39:14761–14767.PubMedGoogle Scholar
  76. Kolmo, T., Kim, J. I., Kobayashi, K., Kodera, Y., Maeda, T. and Sato, K., 1995, Three-dimensional structure in solution of the calcium channel blocker ω-conotoxin MVIIA, Biochemistry 34:10256–10265.Google Scholar
  77. Koradi, R., Billeter, M., and Wüthrich, K., 1996, MOLMOL: a program for display and analysis of macromolecular structures, J Mol Graph 14:51–55, 29–32.PubMedGoogle Scholar
  78. Kutzki, O., Park, H. S., Ernst, J. T., Orner, B. P., Yin, H. and Hamilton, A. D., 2002, Development of a potent Bel-x( L) antagonist based on α-helix mimicry, J Am Chem Soc 124:11838–11839.PubMedGoogle Scholar
  79. Kuwada, M., Teramoto, T., Kumagaye, K. Y., Nakajima, K., Watanabe, T., Kawai, T., Kawakami, Y., Niidome, T., Sawada, K, Nishizawa, Y. and et al., 1994, ω-agatoxin-TK containing D-serine at position 46, but not synthetic ω-[L-Ser46]agatoxin-TK, exerts blockade of P-type calcium channels in cerebellar Purkinje neurons, Mol Pharmacol 46:587–593.PubMedGoogle Scholar
  80. Lampe, R. A, Defeo, P. A, Davison, M. D., Young, J., Herman, J. L., Spreen, R. C., Horn, M. B., Mangano, T. J. and Keith, R. A, 1993, Isolation and pharmacological characterization of ω-grammotoxin SIA, a novel peptide inhibitor of neuronal vohage-sensitive calcium channel responses, Mol Pharmacol 44:451–460.PubMedGoogle Scholar
  81. Leao, R. M., Cruz, J. S., Diniz, C. R., Cordeiro, M. N. and Beirao, P. S., 2000, Inhibition of neuronal high-voltage activated calcium channels by the ω-Phoneutria nigriventer Tx3-3 peptide toxin, Neuropharmacology 39:1756–1767.PubMedGoogle Scholar
  82. Lew, M. J., Flinn, J. P., Pallaghy, P. K, Murphy, R., Whorlow, S. L., Wright, C. E., Norton, R. S. and Angus, J. A, 1997, Structure-function relationships of ω-conotoxin GVIA Synthesis, structure, calcium channel binding, and functional assay of alanine-substituted analogues, J Biol Chem 272:12014–12023.PubMedGoogle Scholar
  83. Lewis, R. J., Nielsen, K J., Craik, D. J., Lougiman, M. L., Adarns, D. A, Sharpe, I.A, Luchian, T., Adams, D. J., Bond, T., Thomas, L., Jones, A, Matheson, J. L., Drinkwater, R., Andrews, P. R. and Alewood, P. F., 2000, Novel ω-conotoxins from Conus catus discriminate among neuronal calcium channel subtypes, J Biol Chem 275:35335–35344.PubMedGoogle Scholar
  84. Liang H., and Elmslie, K.S., 2002, Rapid and reversible block of N-type calcium channels (Cav 2.2) by ω-conotoxin GVIA in the absence of divalent cations. J Neurosci 15:8884–8890.Google Scholar
  85. Liang, S. P., Zhang, D. Y., Pan, X., Chen, Q. and Zhou, P. A, 1993, Properties and amino acid sequence of huwentoxin-I, a neurotoxin purified from the venom of the Chinese bird spider Selenocosmia huwena, Toxicon 31:969–978.PubMedGoogle Scholar
  86. Li-Smerin, Y. and Swartz, K J., 1998, Gating modifier toxins reveal a conserved structural motif in voltage-gated Ca2+ and K+ channels, Proc Natl Acad Sci USA 95:8585–8589.PubMedGoogle Scholar
  87. Lu, B.-S., Yu, F., Zhao, D., Huang, P.-T., Huang, C.-F., 1999, Conopeptides from Conus striatus and Conus textile by cDNA cloning. Peptides 20:1139–1144.PubMedGoogle Scholar
  88. Lukyanetz, E. A, Shkryl, V. M. and Kostyuk, P. G., 2002, Selective blockade of N-type calcium channels by levetiracetam, Epilepsia 43:9–18.PubMedGoogle Scholar
  89. McDonough, S. I., Boland, L. M., Mintz, I.M. and Bean, B. P., 2002, Interactions among toxins that inhibit N-type and P-type calcium channels, J Gen Physiol 119:313–328.PubMedGoogle Scholar
  90. McDonough, S. I., Lampe, R. A, Keith, R. A and Bean, B. P., 1997, Vohage-dependent inhibition of N-and P-type calcium channels by the peptide toxin ω-grammotoxin-SIA, Mol Pharmacol 52:1095–1104.PubMedGoogle Scholar
  91. McGuire, D., Bowersox, S., Fellmann, J. D. and Luther, R. R., 1997, Sympatholysis after neuron-specific, N-type, voltage-sensitive calcium channel blockade: first demonstration of N-channel function in humans, J Cardiovasc Pharmacol 30:400–403.PubMedGoogle Scholar
  92. Menzler, S., Bikker, J. A, Suman-Chauhan, N. and Horwell, D. C., 2000, Design and biological evaluation of nonpeptide analogues of ω-conotoxin MVIIA, Bioorg Med Chem Len 10:345–347.Google Scholar
  93. Mer, G., Hietter, H., Kellenberger, C., Renatus, M., Luu, B. and Lefevre, J. F., 1996, Solution structure of PMP-C: a new fold in the group of small serine proteinase inhibitors, J Mol Biol 258:158–171.PubMedGoogle Scholar
  94. Mer, G., Kellenberger, C., Koehl, P., Stote, R, Sorokine, O., Van Dorsselaer, A, Luu, B., Hietter, H. and Lefevre, J. F., 1994, Solution structure of PMP-D2, a 35-residue peptide isolated from the insect Locusta migratoria, Biochemistry 33:15397–15407.PubMedGoogle Scholar
  95. Miles, L. A, Dy, C. Y., Nielsen, J., Barnham, K. J., Hinds, M. G., Olivera, B. M., Bulaj, G. and Norton, R. S., 2002, Structure of a novel P-superfamily spasmodic conotoxin reveals an inhibitory cystine knot motif, J Biol Chem 277:43033–43040.PubMedGoogle Scholar
  96. Minami, K., Raymond, C., Martin-Moutot, N., Ohtake, A., Van Renterghem, C., Takahashi, M., Seagar, M.J, Mori, Y., and Sato, K, 2001, Role of Thr(11) in the binding of ω-conotoxin MVIIC to N-type Ca2+ channels. FEBS Lett 491:127–30PubMedGoogle Scholar
  97. Mintz, I. M., Venema, V. J, Swiderek, K. M., Lee, T. D., Bean, B. P. and Adams, M. E., 1992, P-type calcium channels blocked by the spider toxin ω-Aga-IVA, Nature 355:827–829.PubMedGoogle Scholar
  98. Miranda, D. M., Romano-Silva, M. A, Kalapothakis, E., Diniz, C. R., Cordeiro, M. N., Santos, T. M., Prado, M. A. and Gomez, M. V., 1998, Phoneutria nigriventer toxins block tityustoxin-induced calcium influx in synaptosomes, Neuroreport 9:1371–1373.PubMedGoogle Scholar
  99. Mitchell, S. S., Shon, K J, Foster, M. P., Davis, D. R, Olivera, B.M. and Ireland, C.M., 1998, Three-dimensional solution structure of conotoxin ψ-PIIIE, an acetylcholine gated ion channel antagonist, Biochemistry 37:1215–1220.PubMedGoogle Scholar
  100. Morrissette, J., Beurg, M., Sukhareva, M. and Coronado, R., 1996, Purification and characterization of ryanotoxin, a peptide with actions similar to those of ryanodine, Biophys J 71:707–721.PubMedGoogle Scholar
  101. Mosbah, A., Kharrat, R., Fajloun, Z., Renisio, J. G., Blanc, E., Sabatier, J. M., El Ayeb, M. and Darbon, H., 2000, A new fold in the scorpion toxin family, associated with an activity on a ryanodine-sensitive calcium channel, Proteins 40:436–442.PubMedGoogle Scholar
  102. Nadasdi, L., Yamashiro, D., Chung, D., Tarczy-Hornoch, K, Adriaenssens, P. and Rarnachandran, J., 1995, Structure-activity analysis of a Conus peptide blocker of N-type neuronal calcium channels, Biochemistry 34:8076–8081.PubMedGoogle Scholar
  103. Naerum, L., Norskov-Lauritsen, L., and Oleson, P. H., 2002, Scaffold hopping and optimization towards libraries of glycogen synthasekinase-3 inhibitors, BioorgMed Chem Lett 12: 1525–1528.Google Scholar
  104. Nakakura, N., Hietter, H., Van Dorsselaer, A and Luu, B., 1992, Isolation and structural determination of three peptides from the insect Locusta migratoria. Identification of a deoxyhexose-linked peptide, Eur J Biochem 204:147–153.PubMedGoogle Scholar
  105. Nakayama, K., Kawato, H. C., Inagaki, H. and Ohta, T., 2001, Novel peptidomirnetics of the antifungal cyclic peptide rhodopeptin: design of mimetics utilizing scaffolding methodology, Org Lett 3:3447–3450.PubMedGoogle Scholar
  106. Narasimhan, L., Singh, J., Humblet, C., Guruprasad, K. and Blundell, T., 1994, Snail and spider toxins share a similar tertiary structure and cystine motif, Nat Struct Biol 1:850–852.PubMedGoogle Scholar
  107. Nemoto, N., Kubo, S., Yoshida, T., Chino, N., Kirnura, T., Sakakibara, S., Kyogoku, Y. and Kobayashi, Y., 1995, Solution structure of ω-conotoxin MVIIC determined by NMR, Biochem Biophys Res Commun 207:695–700.PubMedGoogle Scholar
  108. Newcomb, R., Palma, A, Fox, J, Gaur, S., Lau, K, Chung, D., Cong, R, Bell, J. R., Home, B., Nadasdi, L. and et al., 1995, SNX-325, a novel calcium antagonist from the spider Segestria florentina, Biochemistry 34:8341–8347.PubMedGoogle Scholar
  109. Newcomb, R., Szoke, B., Palma, A., Wang, G., Chen, X., Hopkins, W., Cong, R., Miller, J., Urge, L., Tarczy-Homoch, K., Loo, J. A., Dooley, D. J., Nadasdi, L., Tsien, R. W., Lemos, J. and Miljanich, G., 1998, Selective peptide antagonist of the class E calcium channel from the venom of the tarantula Hysterocrates gigas, Biochemistry 37:15353–15362.PubMedGoogle Scholar
  110. Nielsen, K J., Adams, D. A, Alewood, P. F., Lewis, R. J., Thomas, L., Schroeder, T. and Craik, D. J., 1999a, Effects of chirality at Tyr13 on the structure-activity relationships of ω-conotoxins from Conus magus, Biochemistry 38:6741–6751.PubMedGoogle Scholar
  111. Nielsen, K. J, Adams, D., Thomas, L., Bond, T., Alewood, P. F., Craik, D. J. and Lewis, R. J., 1999b, Structure activity relationships of ω-conotoxins MVIIA, MVIIC and 14 loop splice hybrids at N and P/Q-type calcium channels, J Mol Biol 289:1405–1421.PubMedGoogle Scholar
  112. Nielsen, K. J., Schroeder, T., and Lewis, R., 2000, Structure-activity relationships of ω-conotoxins at N-type voltage-sensitive calcium channels, J Mol Recognit 13:55–70.PubMedGoogle Scholar
  113. Nielsen, K. J., Thomas, L., Lewis, R. J, Alewood, P. F., and Craik, D. J, 1996, A consensus structure for ω-conotoxins with different selectivities for voltage-sensitive calcium channel subtypes: comparison of MVIIA, SVIB and SNX-202, J Mol Biol 263:297–310.PubMedGoogle Scholar
  114. Nishio, H., Katoh, E., Yamazaki, T., Inui, T., Nishiuchi, Y. and Kirnura, T., 1999, Structure-activity relationships of calcicludine and dendrotoxin-I, homologous peptides acting on different targets, calcium and potassium channels, Biochem Biophys Res Commun 262:319–321.PubMedGoogle Scholar
  115. Norton, R. S. and Pallaghy, P. K., 1998, The cystine knot structure of ion channel toxins and related polypeptides, Toxicon 36:1573–1583.PubMedGoogle Scholar
  116. Norton, R. S., Pallaghy, P. K., Baell, J. B., Wright, C. E., Lew, M. J., and Angus, J. A., 1999, Polypeptide ω-conotoxin GVIA as a basis for new analgesic and neuroprotective agents, Drug Develop Res 46:206–218.Google Scholar
  117. Olivera B. M., and Cruz, L. J., 2001, Conotoxins, in retrospect, Toxicon 39: 7–14.PubMedGoogle Scholar
  118. Olivera, B. M., Hillyard, D. R., Marsh, M. and Yoshikami, D., 1995, Combinatorial peptide libraries in drug design: lessons from venomous cone snails, Trends Biotechnol 13:422–426.PubMedGoogle Scholar
  119. Olivera, B. M., Miljanich, G. P., Ramachandran, J. and Adams, M. E., 1994, Calcium channel diversity and neurotransmitter release: the ω-conotoxins and ω-agatoxins, Annu Rev Biochem 63:823–867.PubMedGoogle Scholar
  120. Olivera, B. M., Rivier, J., Clark, C., Ramilo, C. A, Corpuz, G. P., Abogadie, F.C., Mena, E. E., Woodward, S. R, HilIyard, D. R. and Cruz, L. J., 1990, Diversity of Conus neuropeptides, Science 249:257–263.PubMedGoogle Scholar
  121. Oprea, T. I., Davis, A. M., Teague, S. J. and Leeson, P. D., 2001, Is there a difference between leads and drugs? A historical perspective, J Chem Inf Comput Sci 41:1308–1315.PubMedGoogle Scholar
  122. Orner, B. P., Ernst, J. T. and Hamilton, A. D., 2001, Toward proteomimetics: terphenyl derivatives as structural and functional mimics of extended regions of an α-helix, J Am Chem Soc 123:5382–5383.PubMedGoogle Scholar
  123. Pallaghy, P. K., Duggan, B. M., Pennington, M. W. and Norton, R. S., 1993, Three-dimensional structure in solution of the calcium channel blocker ω-conotoxin, J Mol Biol 234:405–420.PubMedGoogle Scholar
  124. Pallaghy, P. K., Kurnar, J. R, Miles, L. A., Pennington, M.W., and Norton, R. S., 2003, Non-linear epitope mimicry on complete chiral families of cyclic peptides. Submitted Google Scholar
  125. Pallaghy, P. K., Nielsen, K. J., Craik, D. J. and Norton, R. S., 1994, A common structural motif incorporating a cystine knot and a triple-stranded β-sheet in toxic and inhibitory polypeptides, Protein Sci 3:1833–1839.PubMedGoogle Scholar
  126. Pallaghy, P. K. and Norton, R S., 1999, Refined solution structure of ω-conotoxin GVIA: implications for calcium channel binding, J Pept Res 53:343–351.PubMedGoogle Scholar
  127. Pallaghy, P. K. and Norton, R. S., 2000, The cyclic contryphan motif CPxXPXC, a robust scaffold potentially useful as an ω-conotoxin mimic, Biopolymers 54:173–179.PubMedGoogle Scholar
  128. Pardridge, W. M., 2002, Targeting neurotherapeutic agents through the blood-brain barrier, Arch Neurol 59:35–40.PubMedGoogle Scholar
  129. Peng, K., Chen, X.D. and Liang, S. P., 2001, The effect of huwentoxin-I on Ca2+ channels in differentiated NG108-15 cells, a patch-clamp study, Toxicon 39:491–498.PubMedGoogle Scholar
  130. Perrier, V., Wallace, A. C., Kaneko, K., Safar, J., Prusiner, S. B. and Cohen, F. E., 2000, Mimicking dominant negative inhibition of prion replication through structure-based drug design, Proc Natl Acad Sci USA 97:6073–6078.PubMedGoogle Scholar
  131. Price-Carter, M., Bulaj, G. and Goldenberg, D. P., 2002, Initial disulfide formation steps in the folding of an ω-conotoxin, Biochemistry 41:3507–3519.PubMedGoogle Scholar
  132. Price-Carter, M., Gray, W. R and Goldenberg, D. P., 1996a, Folding of ω-conotoxins. I. Efficient disulfide coupled folding of mature sequences in vitro, Biochemistry 35:15537–15546.PubMedGoogle Scholar
  133. Price-Carter, M., Gray, W. R and Goldenberg, D. P., 1996b, Folding of ω-conotoxins, 2. Influence of precursor sequences and protein disulfide isomerase, Biochemistry 35:15547–15557.PubMedGoogle Scholar
  134. Price-Carter, M., Hull, M. S. and Goldenberg, D. P., 1998, Roles of individual disulfide bonds in the stability and folding of an ω-conotoxin, Biochemistry 37:9851–9861.PubMedGoogle Scholar
  135. Pruneau, D. and Angus, J. A, 1990, ω-conotoxin GVIA, the N-type calcium channel inhibitor, is sympatholytic but not vagolytic: consequences for hemodynamics and autonomic reflexes in conscious rabbits, J Cardiovasc Pharmacol 16:675–680.PubMedGoogle Scholar
  136. Qu, Y., Liang, S., Ding, J., Liu, X., Zhang, R. and Gu, X, 1997, Proton nuclear magnetic resonance studies on huwentoxin-I from the venom of the spider Selenocosmia huwena: 2. Three-dimensional structure in solution, J Protein Chem 16:565–574.PubMedGoogle Scholar
  137. Rash, L. D. and Hodgson, W. C., 2002, Pharmacology and biochemistry of spider venoms, Toxicon 40:225–254.PubMedGoogle Scholar
  138. Reily, M. D., Holub, K. E., Gray, W. R, Norris, T. M. and Adams, M. E., 1994, Structure-activity relationships for P-type calcium channel-selective ω-agatoxins, Nat Struct Biol 1:853–856.PubMedGoogle Scholar
  139. Reily, M. D., Thanabal, V. and Adams, M. E., 1995, The solution structure of ω-Aga-IVB, a P-type calcium channel antagonist from venom of the funnel web spider, Agelenopsis aperta, J Biomol NMR 5:122–132.PubMedGoogle Scholar
  140. Rhim, H., Kim, H., Lee, D. Y., Oh, T. H. and Nah, S. Y., 2002, Ginseng and ginsenoside Rg3, a newly identified active ingredient of ginseng, modulate Ca2+ channel currents in rat sensory neurons, Eur J Pharmacol 436:151–158.PubMedGoogle Scholar
  141. Roumelioti, P., Polevaya, L., Zoumpoulakis, P., Giatus, N., Mutule, I., Keivish, T., Zoga, A., Vlahakos, D., lliodromitis, E., Kremastinos, D., Grdadolnik, S. G., Mavrornoustakos, T., and Matsoukas, J., 2002, Design, synthesis and biological evaluation of cyclic angiotensin II analogues with 3,5 side-chain bridges: role of C-terminal aromatic residue and ring cluster for activity and implications in the drug design of AT1 non-peptide antagonists, Bioorg Med Chem Lett 12:2627–2633.PubMedGoogle Scholar
  142. Ryder, T. R, Hu, L. Y., Rafferty, M. F., Lotarski, S. M., Rock, D. M., Stoehr, S. J., Taylor, C. P., Weber, M. L., Miljanich, G. P., Millerman, E. and Szoke, B. G., 2000, Structure-activity relationship at the leucine side chain in a series of N,N-dia1kyldipeptidyl-amines as N-type calcium channel blockers, Drug Des Discov 16:317–322.PubMedGoogle Scholar
  143. Ryder, T., Hu, L.-Y., Rafferty, M. F., Lotarski, S. M., Rock, D. M., Stoehr, S. J., Taylor, C. P., Weber, M. L., Miljanich, G. P., Millerman, E., and Szoke, B. G., 1999a, Structure-activity relationship at the proximal phenyl group in a series of ω-peptidyl N-type calcium channel antagonists, Bioorg Med Chem Lett 9:2453–2458.PubMedGoogle Scholar
  144. Ryder, T., Hu, L.-Y., Rafferty, M. F., Lotarski, S. M., Rock, D. M., Stoehr, S. J., Taylor, C. P., Weber, M. L., Miljanich, G. P., Millerman, E., and Szoke, B. G., 1999b, Multiple parallel synthesis of N, Ndialkyldipeptidylamines as N-type calcium channel blockers, Bioorg Med Chem Lett 9:1813–1818.PubMedGoogle Scholar
  145. Sabo, T., Gilon, C., Shafferman, A, and Elhanaty, E., 1992, in Peptides: Chemistry and Biology. Proceedings of the Twelfth American Peptide Symposium, Smith, J. A, and Rivier, J. E., eds., Escom: Leiden, pp 159–160.Google Scholar
  146. Samso, M., Trujillo, R, Gurrola, G. B., Valdivia, H. H. and Wagenknecht, T., 1999, Three-dimensional location of the imperatoxin A binding site on the ryanodine receptor, J Cell Biol 146:493–499.PubMedGoogle Scholar
  147. Santos, R. G., Diniz, C. R, Cordeiro, M. N. and De Lima, M. E., 1999, Binding sites and actions of Txl, a neurotoxin from the venom of the spider Phoneutria nigriventer, in guinea pig ileum, Braz J Med Biol Res 32:1565–1569.PubMedGoogle Scholar
  148. Sarabu, R., Cooper, J. P., Cook, C. M., Gillespie, P., Perrotta, A V. and Olson, G. L., 1997, Design and synthesis of small molecule interleukin-l receptor antagonists based on a benzene template, Drug Des Discov 15:191–198.Google Scholar
  149. Sasaki, T., Kobayashi, K., Kohno, T., and Sato, K., 2000, Combinatorial synthesis of ω-conotoxin MVIIC analogues and their binding with N-and P/Q-type calcium channels. FEBS Lett 466:125–9.PubMedGoogle Scholar
  150. Sato, K., Ishida, Y., Wakamatsu, K., Kato, R., Honda, H., Ohizumi, Y., Nakamura, H., Ohya, M., Lancelin, J. M., and Kohda, D., 1991, Active site of µ-conotoxin GIIIA, a peptide blocker of muscle sodium channels, J Biol Chem 266:16989–16991.PubMedGoogle Scholar
  151. Sato, K., Raymond, C., Martin-Moutot, N., Sasaki, T., Ohtake, A., Minami, K., Van Renterghem, C., Kiln, J.I., Takahashi, M., and Seagar, M.J., 2000a, Binding of Ala-scanning analogs of ω-conotoxin MVIIC to N-and P/Q-type calcium channels. FEBS Lett 469:147–150PubMedGoogle Scholar
  152. Sato K., Raymond, C., Martin-Moutot, N., Sasaki, T., Ohtake, A., Minami, K., Van Renterghem, C., Takahashi, M., and Seagar, M. J., 2000b, Binding of six chimeric analogs of ω-onotoxin MVIIA and MVIIC to N-and P/Q-type calcium channels, Biophys Res Commun 269:254–256.Google Scholar
  153. Savarin, P., Guenneugues, M., Gilquin, B., Lamthanh, H., Gasparini, S., Zinn-Justin, S. and Menez, A., 1998, Three-dimensional structure of ie179-1-conotoxin PVIIA, a novel potassium channel-blocking toxin from cone snails, Biochemistry 37:5407–5416.PubMedGoogle Scholar
  154. Schelkum, R. M., yuen, P., Malone, T. C., Rock, D. M., Stoehr, S., Szoke, B., and Tarczy-Hornoch, K., 1999, Synthesis and biological activity of substituted bis-(4-hydroxyphenyl)methanes as N·type calcium channel bloekers, Bioorg Med Chem Lett 9:2447–2452.Google Scholar
  155. Schweitz, H., Heurteaux, C., Bois, P., Moinier, D., Romey, G. and Lazdunski, M., 1994, Calcicludine, a venom peptide of the Kunitz-type protease inhibitor family, is a potent blocker of high-threshold Ca2+ channels with a high affinity for L-type channels in cerebellar granule neurons, Proc Natl Acad Set USA 91:878–882.Google Scholar
  156. Scott, D. A, Wright, C. E. and Angus, J. A, 2002, Actions of intrathecal ω-conotoxins CVID, GVIA, MVIIA, and morphine in acute and neuropathic pain in the rat, Eur J Pharmacol 451:279·286.PubMedGoogle Scholar
  157. Scott, R. H., Dolphin, A C., Bindokas, V. P. and Adams, M. E., 1990, Inhibition of neuronal Ca2+ channel currents by the funnel web spider toxin ω-Aga·IA, Mol Pharmacol 38:711–718.PubMedGoogle Scholar
  158. Scott, RH., Gorton, V. J., Harding, L., Patel, D., Pacey, S., Kellenberger, C., Hietter, H. and Bermudez, I., 1997, Inhibition of neuronal high voltage-activated calcium channels by insect peptides: a comparison with the actions of ω-conotoxin GVIA, Neuropharmacology 36:195–208.PubMedGoogle Scholar
  159. Seko, T., Kato, M., Kolmo, H., Ono, S., Hashimura, K, Takenobu, Y., Takimizu, H., Nakai, K., Maegawa, H., Katsube, N. and Toda, M., 2002, L-Cysteine based N-type calcium channel blockers: structure-activity relationships of the C-terminal lipophilic moiety, and oral analgesic efficacy in rat pain models, Bioorg Med Chem Lett 12:2267–2269.PubMedGoogle Scholar
  160. Serone, A. P. and Angus, J. A, 1999, Role of N-type calcium channels in autonomic neurotransmission in guinea-pig isolated left atria, Br J Pharmacol 127:927–934.PubMedGoogle Scholar
  161. Sevilla, P., Bruix, M., Santoro, J., Gago, F., Garcia, A. G. and Rico, M., 1993, Three-dimensional structure of ω-conotoxin GVIA determined by 1H NMR, Biochem Biophys Res Commun 192:1238–1244.PubMedGoogle Scholar
  162. Shapiro, R., Ruiz-Gutierrez, M. and Chen, C. z., 2000, Analysis of the interactions of human ribonuclease inhibitor with angiogenin and ribonuclease A by mutagenesis: importance of inhibitor residues inside versus outside the C-tenninal “hot spot”, J Mol Biol 302:497–519.PubMedGoogle Scholar
  163. Sidaeh, S. S. and Mintz, I.M., 2002, Kurtoxin, a gating modifier of neuronal high-and low-threshold Ca channels, J Neurosci 22:2023–2034.Google Scholar
  164. Skalicky, J. J., Metzler, W. J., Ciesla, D. J., Galdes, A and Pardi, A, 1993, Solution structure of the calcium channel antagonist ω-conotoxin GVIA, Protein Sci 2:1591–1603.PubMedGoogle Scholar
  165. Smith, M. T., Cabot, P. J., Ross, F. B., Robertson, A. D. and Lewis, R. J., 2002, The novel N-typecalcium channel blocker, AM336, produces potent dose-dependent antinociception after intrathecal dosing in rats and inhibits substance P release in rat spinal cord slices, Pain 96:119–127.PubMedGoogle Scholar
  166. Song, Y., Bowersox, S. S., Cormor, D. T., Dooley, D. J., Lotarski, S. M., Malone, T., Miljanich, G., Millerman, E., Rafferty, M. F., Rock, D., Roth, B. D., Sclnnidt, J., Stoehr, S., Szoke, B. G., Taylor, C., Vartanian, M. and Wang, Y. X, 2000, (S)-4-Methyl-2-(methylamino)pentanoic acid [4, 4-bis(4-fluorophenyl)butyl]amide hydrochloride, a novel calcium channel antagonist, is efficacious in several animal models of pain, J Med Chem 43:3474–3477.Google Scholar
  167. Sutton, K. G., and Snutch, T. P., 2002, Gabapentin: A novel analgesic targeting voltage-gated calcium channels, Drug Develop Res 54:167–172.Google Scholar
  168. Sutton, K. G., Siok, C., Stea, A., Zarnponi, G. W., Heck, S. D., Volkmann, R. A, AhIijanian, M. K. and Snutch, T. P., 1998, Inhibition of neuronal calcium channels by a novel peptide spider toxin, DW13.3, Mol Pharmacol 54:407–418.PubMedGoogle Scholar
  169. Takeuchi, K., Park, E., Lee, C., Kim, J., Takahashi, H., Swartz, K. and Shimada, I., 2002, Solution structure of’ ω grammotoxin SIA, a gating modifier of P/Q and N-type Ca2+ channel, J Mol Biol 321:517–526.PubMedGoogle Scholar
  170. Tilley, J. W., Chen, L., Fry, D. C., Emerson, S. D., Powers, G. D., Biondi, D., Varnell, T., Trilles, R., Guthrie, R., Mennona, F., Kaplan, G., LeMahieu, R. A, Canon, M., Han, R.-J., Liu, C.-M., Palermo, R., and Ju, G., 1997, Identification of a small molecule inhibitor of the IL-2/IL-2R receptor interaction which binds to JL-2, J Amer Chem Soc 119:7589–7690.Google Scholar
  171. Vaughan, C. K., Buckle, A M. and Fersht, A. R., 1999, Structural response to mutation at a protein-protein interface, J Mol Biol 286: 1487–1506.PubMedGoogle Scholar
  172. Venema, V. J., Swiderek, K. M., Lee, T. D., Hathaway, G. M. and Adarns, M. E., 1992, Antagonism of synaptosomal calcium channels by subtypes of ω-agatoxins, J Biol Chem 267:2610–2615.PubMedGoogle Scholar
  173. Venkatachalam, C. M., 1968, Stereochemical criteria for polypeptides and proteins. V. Conformation of a system of three linked peptide units, Biopolymers 6:1425–1436.PubMedGoogle Scholar
  174. Volpon, L., Lamthanh, H., Le Gall, F., Menez, A, Lancelin, J. M., 2000, Protein Data Bank submission, accession no. 1GIP/1GIZ.Google Scholar
  175. Wakamatsu, K., Kohda, D., Hatanaka, H., Lancelin, J. M., Ishida, Y., Oya, M., Nakarnura, H., Inagaki, F. and Sato, K., 1992, Structure-activity relationships of µ-conotoxin GIIIA: structure determination of active and inactive sodium channel blocker peptides by NMR and simulated annealing calculations, Biochemistry 31:12577–12684.PubMedGoogle Scholar
  176. Wang, X. H., Cormor, M., Wilson, D., Wilson, H. I., Nicholson, G. M., Smith, R., Shaw, D., Mackay, J. P., Alewood, P. F., Christie, M. J. and King, G. F., 2001, Discovery and structure of a potent and highly specific blocker of insect calcium channels, J Biol Chem 276:40306–40312.PubMedGoogle Scholar
  177. Wang, Y. X, Gao, D., Pettus, M., Phillips, C. and Bowersox, S. S., 2000a, Interactions of intrathecally administered ziconotide, a selective blocker of neuronal N-type voltage-sensitive calcium channels, with morphine on nociception in rats, Pain 84:271–281.PubMedGoogle Scholar
  178. Wang, Y. X, Pettus, M., Gao, D., Phillips, C. and Bowersox, S. S., 2000b, Effects of intrathecal administration of ziconotide, a selective neuronal N-type calcium channel blocker, on mechanical allodynia and heat hyperalgesia in a rat model of postoperative pain, Pain 84:15I–158.Google Scholar
  179. Westenbroek, R. E., Hoskins, L. and Catterall, W. A., 1998, Localization of Ca2+ channel subtypes on rat spinal motor neurons, interneurons, and nerve terminals, J Neurosci 18:6319–6330.PubMedGoogle Scholar
  180. Whorlow, S. L., Angus, J. A and Wright, C. E., 1994, The effects of central administration of ω-conotoxin GVIA on cardiovascular parameters and autonomic reflexes in conscious rabbits, Clin Exp Pharmacol Physiol 21:865–873.PubMedGoogle Scholar
  181. Whorlow, S. L., Angus, J. A. and Wright, C. E., 1996a, Selectivity of ω-conotoxin GVIA for N-type calcium channels in rat isolated small mesenteric arteries, Clin Exp Pharmacol Physiol 23:16–21.PubMedGoogle Scholar
  182. Whorlow, S. L., Loiacono, R. E., Angus, J. A. and Wright, C. E., 1996b, Distribution of N-type Ca2+ channel binding sites in rabbit brain following central administration of ω-conotoxin GVIA, Eur J Pharmacol 315:11–118.PubMedGoogle Scholar
  183. Williams, D. H., and Westwell, M. S., 1998, Aspects of weak interactions, Chem Soc Rev 27:57.Google Scholar
  184. Woppmann, A, Ramachandran, J. and Miljanich, G. P., 1994, Calcium channel subtypes in rat brain: biochemical characterization of the high-affinity receptors for ω-conopeplides SNX-230 (synthetic MVIIC), SNX·183 (SVIB), and SNX-111 (MVIIA), Mol Cell Neurosci 5:350–357.PubMedGoogle Scholar
  185. Wright, C. E. and Angus, J. A, 1995, Hemodynamic and autonomic reflex effects of chronic N-type Ca2+ channel blockade with ω-conotoxin GVIA in conscious nonnotensive and hypertensive rabbits, J Cardiovasc Pharmacol 25:459–468.PubMedGoogle Scholar
  186. Wright, C. E. and Angus, J. A, 1996, Effects of N-, P-and Q-type neuronal calcium channel antagonists on mammalian peripheral neurotransmission, BrJ Pharmacol 119:49–56.Google Scholar
  187. Wright, C. E., Hawkes, A L. and Angus, J. A, 2000a, Postoral hypotension following N-type Ca2+ channel blockade is amplified in experimental hypertension, J Hypertens 18:65–73.PubMedGoogle Scholar
  188. Wright, C. E., Robertson, A. D., Whorlow, S. L. and Angus, J. A, 2000b, Cardiovascular and autonomic effects of ω-conotoxins MVIIA and CVID in conscious rabbits and isolatedtissue assays, Br J Pharmacol 131:1325–1336.PubMedGoogle Scholar
  189. Yan, L. and Adams, M. E., 2000, The spider toxin ω-Aga IIIA defines a high affinity site on neuronal high voltage-activated calcium channels, J Biol Chem 275:21309–21316.PubMedGoogle Scholar
  190. Yan, Y. B., and Zhang, R. Q., 2000, Protein Data Bank submission, accessionno. IFYG.Google Scholar
  191. Yan, Z., Chi, P., Bibb, J. A, Ryan, T. A and Greengard, P., 2002, Roscovitine: a novel regulator of P/Q-type calcium channels and transmitter release in central neurons, J Physiol 540:761–770.PubMedGoogle Scholar
  192. Yang, W., He, H., and Drueckhanuner, D. G., 2001, Computer-guided design in molecular recognition: design and synthesis of a glucopyranose receptor, Angew Chem Int Ed 40:1714–1718.Google Scholar
  193. Yasuda, O., Morimoto, S., Jiang, B., Kuroda, H., Kimura, T., Sakakibara, S., Fukuo, K., Chen, S., Tamatani, M. and Ogihara, T., 1994, FS2, a mamba venom toxin, is a specific blocker of the L-type calcium channels, Artery 21:287–302.PubMedGoogle Scholar
  194. Yu, Ho, Rosen, MoK., Saccomano, N. A, Phillips, D., Volkmann, R. A. and Schreiber, Sot., 1993, Sequential assignment and structure determination of spider toxin ω-Aga-IVB, Biochemistry 32:13123–13129.PubMedGoogle Scholar
  195. Zamudio, F. Z; Conde, R., Arevalo, C., Becerril, B., Martin, B. M., Valdivia, H. H. and Possani, L. D., 1997a, The mechanism of inhibition of ryanodine receptor channels by imperatoxin I, a heterodimeric protein from the scorpion Pandinus imperator Biol Chem 272:11886–11894.Google Scholar
  196. Zamudio, F. Z., Gurrola, G. B., Arevalo, C., Sreekumar, R., Walker, J. W., Valdivia, H. H. and Possani, L. D., 1997b, Primary structure and synthesis of imperatoxin A (IpTx2), a peptide activator of Ca2+ release channels/ryanodine receptors, FEES Lett 405:385–389.Google Scholar

Copyright information

© Springer Science+Business Media New York 2004

Authors and Affiliations

  • Raymond S. Norton
    • 1
  • Jonathan B. Baell
    • 1
  • James A. Angus
    • 2
  1. 1.Water and Eliza Hall Institute of Medical ResearchParkvilleAustralia
  2. 2.Department of PharmacologyUniversity of MelbourneParkvilleAustralia

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