Spider Venomics: Implications for Drug Discovery

References

• Fry BG , RoelantsK, ChampagneDEet al. The toxicogenomic multiverse: convergent recruitment of proteins into animal venoms. Annu. Rev. Genomics Hum. Genet.10 (1), 483–511 (2009).
   PubMedGoogle Scholar
• von Reumont BM , BlankeA, RichterS, AlvarezF, BleidornC, JennerRA. The first venomous crustacean revealed by transcriptomics and functional morphology: remipede venom glands express a unique toxin cocktail dominated by enzymes and a neurotoxin. Mol. Biol. Evol.31 (1), 48–58 (2014).
   PubMed Web of Science ®Google Scholar
• Berkov A , RodriguezN, CentenoP. Convergent evolution in the antennae of a cerambycid beetle, Onychocerus albitarsis, and the sting of a scorpion. Naturwissenschaften95 (3), 257–261 (2008).
   PubMedGoogle Scholar
• Platnick NI . Advances in spider taxonomy, 1992–1995: with redescriptions 1940–1980. New York Entomological Society & The American Museum of Natural History, NY, USA (2011). Updated information and statistics available athttp://www.wsc.nmbe.ch/statistics/
   Google Scholar
• Escoubas P , BosmansF. Spider peptide toxins as leads for drug development. Expert Opin. Drug Discov.2 (6), 823–835 (2007).
   PubMed Web of Science ®Google Scholar
• King GF , HardyMC. Spider-venom peptides: structure, pharmacology, and potential for control of insect pests. Annu. Rev. Entomol.58, 475–496 (2013).
   PubMed Web of Science ®Google Scholar
• Rash LD , HodgsonWC. Pharmacology and biochemistry of spider venoms. Toxicon40 (3), 225–254 (2002).
   PubMed Web of Science ®Google Scholar
• King GF . The wonderful world of spiders: preface to the special Toxicon issue on spider venoms. Toxicon43 (5), 471–475 (2004).
   PubMed Web of Science ®Google Scholar
• Escoubas P , SollodB, KingGF. Venom landscapes: mining the complexity of spider venoms via a combined cDNA and mass spectrometric approach. Toxicon47 (6), 650–663 (2006).
   PubMed Web of Science ®Google Scholar
• Kuhn-Nentwig L , StöcklinR, NentwigW. Venom composition and strategies in spiders: is everything possible?Adv. Insect Physiol.40, 1–86 (2011).
   Web of Science ®Google Scholar
• King GF . Venoms to drugs: translating venom peptides into therapeutics. Aust. Biochem.44 (3), 13–15 (2013).
   Google Scholar
• King GF . Venoms as a platform for human drugs: translating toxins into therapeutics. Expert Opin. Biol. Ther.11 (11), 1469–1484 (2011).
   PubMed Web of Science ®Google Scholar
• Vetter I , DavisJL, RashLDet al. Venomics: a new paradigm for natural products-based drug discovery. Amino Acids40, 15–28 (2011).
   PubMed Web of Science ®Google Scholar
• Escoubas P , QuintonL, NicholsonGM. Venomics: unravelling the complexity of animal venoms with mass spectrometry. J. Mass Spectrom.43 (3), 279–295 (2008).
   PubMed Web of Science ®Google Scholar
• Dutertre S , JinAH, KaasQ, JonesA, AlewoodPF, LewisRJ. Deep venomics reveals the mechanism for expanded peptide diversity in cone snail venom. Mol. Cell. Proteomics12 (2), 312–329 (2013).
   PubMed Web of Science ®Google Scholar
• Herzig V , WoodDLA, NewellFet al. ArachnoServer 2.0, an updated online resource for spider toxin sequences and structures Nucleic Acids Res. 39, D653–D657 (2011).
   PubMed Web of Science ®Google Scholar
• Pallaghy PK , NielsenKJ, CraikDJ, NortonRS. A common structural motif incorporating a cystine knot and a triple-stranded β-sheet in toxic and inhibitory polypeptides. Protein Sci.3, 1833–1839 (1994).
   PubMed Web of Science ®Google Scholar
• King GF , TedfordHW, MaggioF. Structure and function of insecticidal neurotoxins from Australian funnel-web spiders. J. Toxicol. Toxin Rev.21, 359–389 (2002).
   Web of Science ®Google Scholar
• Vassilevski AA , KozlovSA, GrishinEV. Molecular diversity of spider venom. Biochemistry (Moscow)74 (13), 1505–1534 (2009).
   PubMed Web of Science ®Google Scholar
• Saez NJ , SenffS, JensenJEet al. Spider-venom peptides as therapeutics. Toxins2, 2851–2871 (2010).
   PubMed Web of Science ®Google Scholar
• Colgrave ML , CraikDJ. Thermal, chemical, and enzymatic stability of the cyclotide kalata B1: the importance of the cyclic cystine knot. Biochemistry43 (20), 5965–5975 (2004).
   PubMed Web of Science ®Google Scholar
• Fletcher JI , SmithR, O’DonoghueSIet al. The structure of a novel insecticidal neurotoxin, ω-atracotoxin-HV1, from the venom of an Australian funnel web spider. Nat. Struct. Biol.4, 559–566 (1997).
   PubMedGoogle Scholar
• Perola E . An analysis of the binding efficiencies of drugs and their leads in successful drug discovery programs. J. Med. Chem.53 (7), 2986–2997 (2010).
   PubMed Web of Science ®Google Scholar
• Gui J , LiuB, CaoGet al. A tarantula-venom peptide antagonizes the TRPA1 nociceptor ion channel by binding to the S1–S4 gating domain. Curr. Biol.24 (5), 473–483 (2014).
   PubMed Web of Science ®Google Scholar
• Frontali N , CeccarelliB, GorioAet al. Purification from black widow spider venom of a protein factor causing the depletion of synaptic vesicles at neuromuscular junctions. J. Cell Biol.68 (3), 462–479 (1976).
   PubMed Web of Science ®Google Scholar
• Sheumack DD , ClaassensR, WhiteleyNM, HowdenME. Complete amino acid sequence of a new type of lethal neurotoxin from the venom of the funnel-web spider Atrax robustus. FEBS Lett.181 (1), 154–156 (1985).
   PubMed Web of Science ®Google Scholar
• Brown MR , SheumackDD, TylerMI, HowdenME. Amino acid sequence of versutoxin, a lethal neurotoxin from the venom of the funnel-web spider Atrax versutus. Biochem. J.250 (2), 401–405 (1988).
   PubMed Web of Science ®Google Scholar
• Kiyatkin NI , DulubovaIE, ChekhovskayaIA, GrishinEV. Cloning and structure of cDNA encoding α-latrotoxin from black widow spider venom. FEBS Lett.270 (1–2), 127–131 (1990).
   PubMed Web of Science ®Google Scholar
• Frohman MA , DushMK, MartinGR. Rapid production of full-length cDNAs from rare transcripts: amplification using a single gene-specific oligonucleotide primer. Proc. Natl Acad. Sci. USA85 (23), 8998–9002 (1988).
   PubMed Web of Science ®Google Scholar
• Wang X-H , ConnorM, WilsonDet al. Discovery and structure of a potent and highly specific blocker of insect calcium channels. J. Biol. Chem.276 (43), 40306–40312 (2001).
   PubMed Web of Science ®Google Scholar
• Diao JB , LinY, TangJZ, LiangSP. cDNA sequence analysis of seven peptide toxins from the spider Selenocosmia huwena. Toxicon42 (7), 715–723 (2003).
   PubMed Web of Science ®Google Scholar
• Sollod BL , WilsonD, ZhaxybayevaO, GogartenJP, DrinkwaterR, KingGF. Were arachnids the first to use combinatorial peptide libraries?Peptides26 (1), 131–139 (2005).
   PubMed Web of Science ®Google Scholar
• Kozlov S , GrishinEV. Classification of spider neurotoxins using structural motifs by primary structure features. Single residue distribution analysis and pattern analysis techniques. Toxicon46 (6), 672–686 (2005).
   PubMed Web of Science ®Google Scholar
• Chen J , ZhaoL, JiangLet al. Transcriptome analysis revealed novel possible venom components and cellular processes of the tarantula Chilobrachys jingzhao venom gland. Toxicon52 (7), 794–806 (2008).
   PubMed Web of Science ®Google Scholar
• Tang X , ZhangY, HuWet al. Molecular diversification of peptide toxins from the tarantula Haplopelma hainanum (Ornithoctonus hainana) venom based on transcriptomic, peptidomic, and genomic analyses. J. Proteome Res.9 (5), 2550–2564 (2010).
   PubMed Web of Science ®Google Scholar
• Jiang L , ChenJ, PengL, ZhangY, XiongX, LiangS. Genomic organization and cloning of novel genes encoding toxin-like peptides of three superfamilies from the spider Orinithoctonus huwena. Peptides29 (10), 1679–1684 (2008).
   PubMed Web of Science ®Google Scholar
• Gremski LH , da SilveiraRB, ChaimOMet al. A novel expression profile of the Loxosceles intermedia spider venomous gland revealed by transcriptome analysis. Mol. Biosyst.6 (12), 2403–2416 (2010).
   PubMedGoogle Scholar
• Fernandes-Pedrosa MdF , Junqueira-de-AzevedoIdLM, Goncalves-de-AndradeRMet al. Transcriptome analysis of Loxosceles laeta (Araneae, Sicariidae) spider venomous gland using expressed sequence tags. BMC Genomics9, 279 (2008).
   PubMed Web of Science ®Google Scholar
• Zhang Y , ChenJ, TangXet al. Transcriptome analysis of the venom glands of the Chinese wolf spider Lycosa singoriensis. Zoology113 (1), 10–18 (2010).
   PubMed Web of Science ®Google Scholar
• Diego-Garcia E , PeigneurS, WaelkensE, DebaveyeS, TytgatJ. Venom components from Citharischius crawshayi spider (Family Theraphosidae): exploring transcriptome, venomics, and function. Cell. Mol. Life Sci.67 (16), 2799–2813 (2010).
   PubMed Web of Science ®Google Scholar
• Wong ES , HardyMC, WoodD, BaileyT, KingGF. SVM-based prediction of propeptide cleavage sites in spider toxins identifies toxin innovation in an Australian tarantula. PLoS ONE8 (7), e66279 (2013).
   PubMed Web of Science ®Google Scholar
• Undheim EA , SunagarK, HerzigVet al. A proteomics and transcriptomics investigation of the venom from the barychelid spider Trittame loki (brush-foot trapdoor). Toxins5 (12), 2488–2503 (2013).
   PubMed Web of Science ®Google Scholar
• He Q , DuanZ, YuY, LiuZ, LiuZ, LiangS. The venom gland transcriptome of Latrodectus tredecimguttatus revealed by deep sequencing and cDNA library analysis. PLoS ONE8 (11), e81357 (2013).
   PubMed Web of Science ®Google Scholar
• Sanggaard KW , BechsgaardJS, FangXet al. Spider genomes provide insight into composition and evolution of venom and silk. Nat. Commun.5, 3765 (2014).
   PubMed Web of Science ®Google Scholar
• Gregory TR , ShorthouseDP. Genome sizes of spiders. J. Heredity94, 285–290 (2003).
   PubMed Web of Science ®Google Scholar
• Davis J , JonesA, LewisRJ. Remarkable inter- and intra-species complexity of conotoxins revealed by LC/MS. Peptides30 (7), 1222–1227 (2009).
   PubMed Web of Science ®Google Scholar
• Bandeira N , ClauserKR, PevznerPA. Shotgun protein sequencing: assembly of peptide tandem mass spectra from mixtures of modified proteins. Mol. Cell. Proteomics6 (7), 1123–1134 (2007).
   PubMed Web of Science ®Google Scholar
• Ueberheide BM , FenyoD, AlewoodPF, ChaitBT. Rapid sensitive analysis of cysteine rich peptide venom components. Proc. Natl Acad. Sci. USA106 (17), 6910–6915 (2009).
   PubMed Web of Science ®Google Scholar
• Perkins DN , PappinDJC, CreasyDM, CottrellJS. Probability-based protein identification by searching sequence databases using mass spectrometry data. Electrophoresis20 (18), 3551–3567 (1999).
   PubMed Web of Science ®Google Scholar
• Craig R , BeavisRC. TANDEM: matching proteins with tandem mass spectra. Bioinformatics20 (9), 1466–1467 (2004).
   PubMed Web of Science ®Google Scholar
• Zobel-Thropp PA , CorreaSM, GarbJE, BinfordGJ. Spit and venom from Scytodes spiders: a diverse and distinct cocktail. J. Proteome Res.13 (2), 817–835 (2013).
   PubMed Web of Science ®Google Scholar
• Duan Z , CaoR, JiangL, LiangS. A combined de novo protein sequencing and cDNA library approach to the venomic analysis of Chinese spider Araneus ventricosus. J. Proteomics78, 416–427 (2013).
   PubMed Web of Science ®Google Scholar
• Craik DJ , AdamsDJ. Chemical modification of conotoxins to improve stability and activity. ACS Chem. Biol.2 (7), 457–468 (2007).
   PubMed Web of Science ®Google Scholar
• Muttenthaler M , AkondiKB, AlewoodPF. Structure-activity studies on α-conotoxins. Curr. Pharm. Des.17 (38), 4226–4241 (2011).
   PubMed Web of Science ®Google Scholar
• Revell JD , LundPE, LinleyJEet al. Potency optimization of huwentoxin-IV on hNav1.7: a neurotoxin TTX-S sodium-channel antagonist from the venom of the Chinese bird-eating spider Selenocosmia huwena. Peptides44, 40–46 (2013).
   PubMed Web of Science ®Google Scholar
• Dawson PE , MuirTW, Clark-LewisI, KentSBH. Synthesis by native chemical ligation. Science266, 776–779 (1994).
   PubMed Web of Science ®Google Scholar
• Jensen JE , DurekT, AlewoodPF, AdamsDJ, KingGF, RashLD. Chemical synthesis and folding of APETx2, a potent and selective inhibitor of acid sensing ion channel 3. Toxicon54 (1), 56–61 (2009).
   PubMed Web of Science ®Google Scholar
• Durek T , VetterI, WangC-IAet al. Chemical engineering and structural and pharmacological characterization of the α-scorpion toxin OD1. ACS Chem. Biol.8 (6), 1215–1222 (2013).
   PubMed Web of Science ®Google Scholar
• Schroeder CI , RashLD, Vila-FarrésXet al. Chemical synthesis, 3D structure, and ASIC binding site of the toxin mambalgin-2. Angew. Chem. Int. Ed.53 (4), 1017–1020 (2014).
   PubMed Web of Science ®Google Scholar
• Bulaj G , OliveraBM. Folding of conotoxins: formation of the native disulfide bridges during chemical synthesis and biosynthesis of Conus peptides. Antioxid. Redox Signal.10 (1), 141–155 (2008).
   PubMed Web of Science ®Google Scholar
• Anangi R , ChenC-Y, ChengC-Het al. Expression of snake venom toxins in Pichia pastoris. Toxin Rev.26, 169–187 (2007).
   Web of Science ®Google Scholar
• Makrides SC . Strategies for achieving high-level expression of genes in Escherichia coli. Microbiol. Rev.60 (3), 512–538 (1996).
   PubMedGoogle Scholar
• Baneyx F , MujacicM. Recombinant protein folding and misfolding in Escherichia coli. Nat. Biotech.22 (11), 1399–1408 (2004).
   PubMed Web of Science ®Google Scholar
• Tedford HW , FletcherJI, KingGF. Functional significance of the β-hairpin in the insecticidal neurotoxin ω-atracotoxin-Hv1a. J. Biol. Chem.276, 26568–26576 (2001).
   PubMed Web of Science ®Google Scholar
• Klint JK , SenffS, SaezNJet al. Production of recombinant disulfide-rich venom peptides for structural and functional analysis via expression in the periplasm of E. coli. PLoS ONE8 (5), e63865 (2013).
   PubMed Web of Science ®Google Scholar
• Ito K , InabaK. The disulfide bond formation (Dsb) system. Curr. Opin. Struct. Biol.18 (4), 450–458 (2008).
   PubMed Web of Science ®Google Scholar
• Heras B , ShouldiceSR, TotsikaM, ScanlonMJ, SchembriMA, MartinJL. DSB proteins and bacterial pathogenicity. Nat. Rev. Microbiol.7 (3), 215–225 (2009).
   PubMed Web of Science ®Google Scholar
• Kwan AH , MobliM, GooleyPR, KingGF, MackayJP. Macromolecular NMR spectroscopy for the non-spectroscopist. FEBS J.278 (5), 687–703 (2011).
   PubMed Web of Science ®Google Scholar
• Dawson RJ , BenzJ, StohlerPet al. Structure of the acid-sensing ion channel 1 in complex with the gating modifier psalmotoxin 1. Nat. Commun.3, 936 (2012).
   PubMed Web of Science ®Google Scholar
• Baconguis I , GouauxE. Structural plasticity and dynamic selectivity of acid-sensing ion channel-spider toxin complexes. Nature489 (7416), 400–405 (2012).
   PubMed Web of Science ®Google Scholar
• Cao E , LiaoM, ChengY, JuliusD. TRPV1 structures in distinct conformations reveal activation mechanisms. Nature504 (7478), 113–118 (2013).
   PubMed Web of Science ®Google Scholar
• Mobli M , MaciejewskiMW, GrykMR, HochJC. An automated tool for maximum entropy reconstruction of biomolecular NMR spectra. Nat. Methods4 (6), 467–468 (2007).
   PubMed Web of Science ®Google Scholar
• Mobli M , SternAS, BermelW, KingGF, HochJC. A non-uniformly sampled 4D HCC(CO)NH-TOCSY experiment processed using maximum entropy for rapid protein sidechain assignment. J. Magn. Reson.204, 160–164 (2010).
   PubMed Web of Science ®Google Scholar
• Güntert P . Automated NMR structure calculation with CYANA. Methods Mol. Biol.278, 353–378 (2004).
   PubMedGoogle Scholar
• Saez NJ , MobliM, BieriMet al. A dynamic pharmacophore drives the interaction between psalmotoxin-1 and the putative drug target acid-sensing ion channel 1a. Mol. Pharmacol.80, 796–808 (2011).
   PubMed Web of Science ®Google Scholar
• Bende NS , KangE, HerzigVet al. The insecticidal neurotoxin Aps III is an atypical knottin peptide that potently blocks insect voltage-gated sodium channels. Biochem. Pharmacol.85 (10), 1542–1554 (2013).
   PubMed Web of Science ®Google Scholar
• Cunningham BC , WellsJA. High-resolution epitope mapping of hGH-receptor interactions by alanine-scanning mutagenesis. Science244 (4908), 1081–1085 (1989).
   PubMed Web of Science ®Google Scholar
• Maggio F , KingGF. Scanning mutagenesis of a Janus-faced atracotoxin reveals a bipartite surface patch that is essential for neurotoxic function. J. Biol. Chem.277, 22806–22813 (2002).
   PubMed Web of Science ®Google Scholar
• Tedford HW , GillesN, MénezA, DoeringCJ, ZamponiGW, KingGF. Scanning mutagenesis of ω-atracotoxin-Hv1a reveals a spatially restricted epitope that confers selective activity against invertebrate calcium channels. J. Biol. Chem.279, 44133–44140 (2004).
   PubMed Web of Science ®Google Scholar
• Corzo G , SaboJK, BosmansFet al. Solution structure and alanine scan of a spider toxin that affects the activation of mammalian voltage-gated sodium channels. J. Biol. Chem.282 (7), 4643–4652 (2007).
   PubMed Web of Science ®Google Scholar
• Estrada G , VillegasE, CorzoG. Spider venoms: a rich source of acylpolyamines and peptides as new leads for CNS drugs. Nat. Prod. Rep.24 (1), 145–161 (2007).
   PubMed Web of Science ®Google Scholar
• Windley MJ , HerzigV, DziemborowiczSA, HardyMC, KingGF, NicholsonGM. Spider-venom peptides as bioinsecticides. Toxins4 (3), 191–227 (2012).
   PubMed Web of Science ®Google Scholar
• Catterall WA , GoldinAL, WaxmanSG. International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol. Rev.57 (4), 397–409 (2005).
   PubMed Web of Science ®Google Scholar
• Yu FH , CatterallWA. Overview of the voltage-gated sodium channel family. Genome Biol.4, 207 (2003).
   PubMed Web of Science ®Google Scholar
• King GF , EscoubasP, NicholsonGM. Peptide toxins that selectively target insect NaV and CaV channels. Channels2 (2), 100–116 (2008).
   PubMed Web of Science ®Google Scholar
• Waxman SG , Dib-HajjS. Erythermalgia: molecular basis for an inherited pain syndrome. Trends Mol. Med.11 (12), 555–562 (2005).
   PubMed Web of Science ®Google Scholar
• Rush AM , Dib-HajjSD, LiuSJ, CumminsTR, BlackJA, WaxmanSG. A single sodium channel mutation produces hyperor hypoexcitability in different types of neurons. Proc. Natl Acad. Sci. USA103, 8245–8250 (2006).
   PubMed Web of Science ®Google Scholar
• Jarecki BW , SheetsPL, JacksonJO, CumminsTR. Paroxysmal extreme pain disorder mutations within the D3/S4-S5 linker of Nav1.7 cause moderate destabilization of fast inactivation. J. Physiol.586 (17), 4137–4153 (2008).
   PubMed Web of Science ®Google Scholar
• Cox JJ , ReimannF, NicholasAKet al. An SCN9A channelopathy causes congenital inability to experience pain. Nature444 (7121), 894–898 (2006).
   PubMed Web of Science ®Google Scholar
• Weiss J , PyrskiM, JacobiEet al. Loss-of-function mutations in sodium channel Nav1.7 cause anosmia. Nature472 (7342), 186–190 (2011).
   PubMed Web of Science ®Google Scholar
• Rupasinghe DB , KnappO, BlomsterLVet al. Localization of NaV1.7 in the normal and injured rodent olfactory system indicates a critical role in olfaction, pheromone sensing and immune function. Channels6, 103–110 (2012).
   PubMed Web of Science ®Google Scholar
• Reimann F , CoxJJ, BelferIet al. Pain perception is altered by a nucleotide polymorphism in SCN9A. Proc. Natl Acad. Sci. USA107 (11), 5148–5153 (2010).
   PubMed Web of Science ®Google Scholar
• Duan G , XiangG, ZhangX, YuanR, ZhanH, QiD. A single-nucleotide polymorphism in SCN9A may decrease postoperative pain sensitivity in the general population. Anesthesiology118, 436–442 (2013).
   PubMed Web of Science ®Google Scholar
• Clare JJ . Targeting voltage-gated sodium channels for pain therapy. Expert Opin. Investig. Drugs19 (1), 45–62 (2010).
   PubMed Web of Science ®Google Scholar
• England S , RawsonD. Isoform-selective voltage-gated Na+ channel modulators as next-generation analgesics. Future Med. Chem.2 (5), 775–790 (2010).
   PubMed Web of Science ®Google Scholar
• Catterall WA . From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron26 (1), 13–25 (2000).
   PubMed Web of Science ®Google Scholar
• Krafte DS , BannonAW. Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol.8 (1), 50–56 (2008).
   PubMed Web of Science ®Google Scholar
• Klint JK , SenffS, RupasingheDBet al. Spider-venom peptides that target voltage-gated sodium channels: pharmacological tools and potential therapeutic leads. Toxicon60 (4), 478–491 (2012).
   PubMed Web of Science ®Google Scholar
• Schmalhofer WA , CalhounJ, BurrowsRet al. ProTx-II, a selective inhibitor of NaV1.7 sodium channels, blocks action potential propagation in nociceptors. Mol. Pharmacol.74 (5), 1476–1484 (2008).
   PubMed Web of Science ®Google Scholar
• Bosmans F , RashL, ZhuSYet al. Four novel tarantula toxins as selective modulators of voltage-gated sodium channel subtypes. Mol. Pharmacol.69 (2), 419–429 (2006).
   PubMed Web of Science ®Google Scholar
• Ono S , KimuraT, KuboT. Characterization of voltage-dependent calcium channel blocking peptides from the venom of the tarantula Grammostola rosea. Toxicon58 (3), 265–276 (2011).
   PubMed Web of Science ®Google Scholar
• King GF , GentzMC, EscoubasP, NicholsonGM. A rational nomenclature for naming peptide toxins from spiders and other venomous animals. Toxicon52 (2), 264–276 (2008).
   PubMed Web of Science ®Google Scholar
• ArachnoServer . www.arachnoserver.org/toxincard.html?id=AS-Card-Number
   Google Scholar
• King GF . Modulation of insect CaV channels by peptidic spider toxins. Toxicon49 (4), 513–530 (2007).
   PubMed Web of Science ®Google Scholar
• Altier C , ZamponiGW. Targeting Ca2+ channels to treat pain: T-type versus N-type. Trends Pharmacol. Sci.25 (9), 465–470 (2004).
   PubMed Web of Science ®Google Scholar
• McGivern JG , McDonoughSI. Voltage-gated calcium channels as targets for the treatment of chronic pain. Curr. Drug Targets CNS Neurol. Disord.3 (6), 457–478 (2004).
   PubMedGoogle Scholar
• Deng M , LuoX, XiaoYet al. Huwentoxin-XVI, an analgesic, highly reversible mammalian N-type calcium channel antagonist from Chinese tarantula Ornithoctonus huwena. Neuropharmacology79, 657–667 (2014).
   PubMed Web of Science ®Google Scholar
• Miljanich GP . Ziconotide: neuronal calcium channel blocker for treating severe chronic pain. Curr. Med. Chem.11 (23), 3029–3040 (2004).
   PubMed Web of Science ®Google Scholar
• McNamara CR , Mandel-BrehmJ, BautistaDMet al. TRPA1 mediates formalin-induced pain. Proc. Natl Acad. Sci. USA104 (33), 13525–13530 (2007).
   PubMed Web of Science ®Google Scholar
• Lewis RJ , DutertreS, VetterI, ChristieMJ. Conus venom peptide pharmacology. Pharmacol. Rev.64 (2), 259–298 (2012).
   PubMed Web of Science ®Google Scholar
• Kellenberger S , SchildL. Epithelial sodium channel/degenerin family of ion channels: a variety of functions for a shared structure. Physiol. Rev.82 (3), 735–767 (2002).
   PubMed Web of Science ®Google Scholar
• Lingueglia E . Acid-sensing ion channels in sensory perception. J. Biol. Chem.282 (24), 17325–17329 (2007).
   PubMed Web of Science ®Google Scholar
• Sluka KA , WinterOC, WemmieJA. Acid-sensing ion channels: a new target for pain and CNS diseases. Curr. Opin. Drug Discov. Dev.12 (5), 693–704 (2009).
   PubMedGoogle Scholar
• Voilley N . Acid-sensing ion channels (ASICs): new targets for the analgesic effects of non-steroid anti-inflammatory drugs (NSAIDs). Curr. Drug Targets Inflamm. Allergy3 (1), 71–79 (2004).
   PubMedGoogle Scholar
• Gwanyanya A , MacianskieneR, MubagwaK. Insights into the effects of diclofenac and other non-steroidal anti-inflammatory agents on ion channels. J. Pharm. Pharmacol.64 (10), 1359–1375 (2012).
   PubMed Web of Science ®Google Scholar
• Escoubas P , De WeilleJR, LecoqAet al. Isolation of a tarantula toxin specific for a class of proton-gated Na+ channels. J. Biol. Chem.275 (33), 25116–25121 (2000).
   PubMed Web of Science ®Google Scholar
• Mazzuca M , HeurteauxC, AllouiAet al. A tarantula peptide against pain via ASIC1a channels and opioid mechanisms. Nat. Neurosci.10 (8), 943–945 (2007).
   PubMed Web of Science ®Google Scholar
• Smith HS . Intrathecal drug delivery. Pain Physician11, S89–S104 (2008).
   PubMed Web of Science ®Google Scholar
• Tedford HW , SteinbaughBA, BaoLet al. In silico screening for compounds that match the pharmacophore of ω-hexatoxin-Hv1a leads to discovery and optimization of a novel class of insecticides. Pesticide Biochem. Physiol.106, 124–140 (2013).
   Web of Science ®Google Scholar
• Moskowitz MA , LoEH, IadecolaC. The science of stroke: mechanisms in search of treatments. Neuron67 (2), 181–198 (2010).
   PubMed Web of Science ®Google Scholar
• Woodruff TM , ThundyilJ, TangSC, SobeyCG, TaylorSM, ArumugamTV. Pathophysiology, treatment, and animal and cellular models of human ischemic stroke. Mol. Neurodegener.6 (1), 11 (2011).
   PubMed Web of Science ®Google Scholar
• Liu R , YuanH, YuanF, YangSH. Neuroprotection targeting ischemic penumbra and beyond for the treatment of ischemic stroke. Neurol. Res.34 (4), 331–337 (2012).
   PubMed Web of Science ®Google Scholar
• Xiong ZG , ChuXP, SimonRP. Acid sensing ion channels – novel therapeutic targets for ischemic brain injury. Front. Biosci.12, 1376–1386 (2007).
   PubMed Web of Science ®Google Scholar
• Xiong ZG , ZhuXM, ChuXPet al. Neuroprotection in ischemia: blocking calcium-permeable acid-sensing ion channels. Cell118 (6), 687–698 (2004).
   PubMed Web of Science ®Google Scholar
• Isaev NK , StelmashookEV, PlotnikovEYet al. Role of acidosis, NMDA receptors, and acid-sensitive ion channel 1a (ASIC1a) in neuronal death induced by ischemia. Biochemistry (Moscow)73 (11), 1171–1175 (2008).
   PubMed Web of Science ®Google Scholar
• Leng TD , XiongZG. The pharmacology and therapeutic potential of small molecule inhibitors of acid-sensing ion channels in stroke intervention. Acta Pharmacol. Sin.34 (1), 33–38 (2013).
   PubMed Web of Science ®Google Scholar
• Pignataro G , SimonRP, XiongZG. Prolonged activation of ASIC1a and the time window for neuroprotection in cerebral ischaemia. Brain130, 151–158 (2007).
   PubMed Web of Science ®Google Scholar
• Ikonomidou C , TurskiL. Why did NMDA receptor antagonists fail clinical trials for stroke and traumatic brain injury?Lancet Neurol.1 (6), 383–386 (2002).
   PubMed Web of Science ®Google Scholar
• Skaper SD , DebettoP, GiustiP. The P2X7 purinergic receptor: from physiology to neurological disorders. FASEB J.24 (2), 337–345 (2010).
   PubMed Web of Science ®Google Scholar
• Nicke A , BaumertHG, RettingerJet al. P2X1 and P2X3 receptors form stable trimers: a novel structural motif of ligand-gated ion channels. EMBO J.17 (11), 3016–3028 (1998).
   PubMed Web of Science ®Google Scholar
• Jarvis MF , BurgardEC, McGaraughtySet al. A-317491, a novel potent and selective nonnucleotide antagonist of P2X3 and P2X2/3 receptors, reduces chronic inflammatory and neuropathic pain in the rat. Proc. Natl Acad. Sci. USA99 (26), 17179–17184 (2002).
   PubMed Web of Science ®Google Scholar
• Hausmann R , RettingerJ, GerevichZet al. The suramin analog 4,4 ’,4 ‘’,4 ‘‘‘-(carbonylbis(imino-5,1,3-benzenetriylbis (carbonylimino)))tetra-kis-benzenesulfonic acid (NF110) potently blocks P2X3 receptors: subtype selectivity is determined by location of sulfonic acid groups. Mol. Pharmacol.69 (6), 2058–2067 (2006).
   PubMed Web of Science ®Google Scholar
• Jung KY , MoonHD, LeeGE, LimHH, ParkCS, KimYC. Structure-activity relationship studies of spinorphin as a potent and selective human P2X3 receptor antagonist. J. Med. Chem.50 (18), 4543–4547 (2007).
   PubMed Web of Science ®Google Scholar
• Grishin EV , SavchenkoGA, VassilevskiAAet al. Novel peptide from spider venom inhibits P2X3 receptors and inflammatory pain. Ann. Neurol.67 (5), 680–683 (2010).
   PubMed Web of Science ®Google Scholar
• Cohen E , QuistadGB. Cytotoxic effects of arthropod venoms on various cultured cells. Toxicon36 (2), 353–358 (1998).
   PubMed Web of Science ®Google Scholar
• Gao L , ShanBE, ChenJ, LiuJH, SongDX, ZhuBC. Effects of spider Macrothele raven venom on cell proliferation and cytotoxicity in HeLa cells. Acta Pharmacol. Sin.26 (3), 369–376 (2005).
   PubMed Web of Science ®Google Scholar
• Gao L , YuS, WuY, ShanB. Effect of spider venom on cell apoptosis and necrosis rates in MCF-7 cells. DNA Cell Biol.26, 485–489 (2007).
   PubMed Web of Science ®Google Scholar
• Liu Z , ZhaoY, LiJet al. The venom of the spider Macrothele raveni induces apoptosis in the myelogenous leukemia K562 cell line. Leuk. Res.36 (8), 1063–1066 (2012).
   PubMed Web of Science ®Google Scholar
• Bubien JK , JiHL, GillespieGYet al. Cation selectivity and inhibition of malignant glioma Na+ channels by Psalmotoxin 1. Am. J. Physiol. Cell Physiol.287, C1282–C1291 (2004).
   PubMed Web of Science ®Google Scholar
• Li M , InoueK, BraniganDet al. Acid-sensing ion channels in acidosis-induced injury of human brain neurons. J. Cereb. Blood Flow Metab.30 (6), 1247–1260 (2010).
   PubMed Web of Science ®Google Scholar
• Deshane J , GarnerCC, SontheimerH. Chlorotoxin inhibits glioma cell invasion via matrix metalloproteinase-2. J. Biol. Chem.278 (6), 4135–4144 (2003).
   PubMed Web of Science ®Google Scholar
• Kesavan K , RatliffJ, JohnsonEWet al. Annexin A2 is a molecular target for TM601, a peptide with tumor-targeting and anti-angiogenic effects. J. Biol. Chem.285 (7), 4366–4374 (2010).
   PubMed Web of Science ®Google Scholar
• Veiseh M , GabikianP, BahramiSBet al. Tumor paint: a chlorotoxin: Cy5.5 bioconjugate for intraoperative visualization of cancer foci. Cancer Res.67 (14), 6882–6888 (2007).
   PubMed Web of Science ®Google Scholar
• Stroud MR , HansenSJ, OlsonJM. In vivo bio-imaging using chlorotoxin-based conjugates. Curr. Pharm. Des.17 (38), 4362–4371 (2011).
   PubMed Web of Science ®Google Scholar