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Pharmacological Research Progress and Prospects of Spider Toxins Especially on Ion Channels

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Pharmacological Research Progress and Prospects of Spider Toxins Especially on Ion Channels www.ijapbc.com IJAPBC – Vol. 4(1), Jan - Mar, 2015 ISSN: 2277 - 4688 INTERNATIONAL JOURNAL OF ADVANCES IN PHARMACY, BIOLOGY AND CHEMISTRY Research Article Pharmacological Research Progress and Prospects of Spider Toxins especially on Ion Channels Guike Li 1, Zizhong Yang 1, Chenggui Zhang 2, Chenggong Li 1, Yuanyuan Zheng 2, Xiumei Wu 1*, Zhibin Yang 2, and Yu Zhao 1,2*. 1 Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, Dali University, Dali 671000, Yunnan Province, China. 2 National-local Joint Engineering Research Center of Entomoceutics, Dali 671000, Yunnan Province, China. ABSTRACT Spider toxins are huge combinatorial libraries composed of natural peptides and proteins with high medicinal values and different medicinal properties, including a variety of pharmacological effects like analgesic, anti-bacterial, insect repellent, anti-tumor, etc. Various toxins acting on different ion channels play different pharmacological efficacies. Along with the in-depth studies of spider toxins in recent years, this biotoxin family is expected to be more widely used in new drug discovery as well as in the treatment of various refractory diseases. Following worldwide research progress in this area, China has also made a unique and significant development in the past decades. This report gave a general review of the above-mentioned researches and the development outlook of this toxin family. Keywords: Biotoxin, cardiovascular diseases, ion channels, natural active components, new drug R&D, pharmacological activities, spider venom. INTRODUCTION The spider, Araneae, is the biggest group except for in defense or hunting 2. Spider venom is composed of insects in terrestrial animals. The Araneae is a large diverse components, whose bioactive effects are also order of Arachnida with about 3935 genera 44906 various. The venom can be used for local ischemia, or described species all over the world 1, while in China used as neuroprotective agents, pesticides, and the estimate is no less than 3,000 species. Many analgesic drugs. Traditional Chinese Medicine spiders discharge venom from their cheliceral claws emphasizes a widely applied remedy called "fight 171 www.ijapbc.com IJAPBC – Vol. 4(1), Jan - Mar, 2015 ISSN: 2277 - 4688 poison with poison". Based on this conception and composed of peptides and proteins, including historically practical experiences, the medicinal polypeptide neurotoxin, cytotoxins, bradykinin spiders were recorded as "to cure all furuncle analogs, antimicrobial peptides, enzymes swollen, suppurative osteomyelitis corrosive sores, (sphingomyelinase, hyaluronidase, phospholipase, polypus and sarcoma" in Chen Zangqi's "Chinese isomerase) and agglutination active peptides. It also Materia Medica" published at Tang dynasty. As a contains low molecular weight substances such as natural toxin, spider toxins hold rich prospects of polyamines, nucleotides, amino acids, monoamines, medical application 3. and inorganic salts 8. Spider venom contains so many ingredients making it possess a huge role in the TYPE AND COMPOSITION OF SPIDER pharmacological efficacies, thus providing a broad TOXINS AND THEIR PHARMACOLOGICAL prospect to take advantage of these biotoxins for the EFFECTS development of new drugs. Type and Composition of Spider Toxins Currently, nearly 500 spider toxins have been In accordance with the role and functions, the spider structurally identified, less than 1% of the speculated toxins could be divided into three categories such as all spider toxins. Scrutiny on the identified toxin nerve poisons, poison necrosis, and mixed poison, components, it could be generally divided into three while the most important of which is neurotoxins 4,5. categories according to molecular weight difference 9. Neurotoxins can be further differentiated into The first class indicated small molecules less than polypeptides and polyamines, and in accordance with 1000 Daltons. This category includes inorganic the difference in molecular size, the peptidic toxins ions/salts (Ca2+, Na+, K+, Mg2+, Cl-, etc.), organic could be subsequently divided into high molecular acids (e.g., citric acid, lactic acid, weight proteins and low molecular weight peptide dihydro-phenylacetic acid), glucose, amino acids, toxins. The high molecular weight toxin protein could biogenic amines (e.g., histamine, spermine, be represented by such as the α-latrotoxin (α-LTX) spermidine, putrescine, etc.), and neurotransmitters isolated from the venom of Latrodectus (glutamate, aspartic acid, epinephrine, dopamine, tredecimguttatus, α-latroerustatoxin (α-LCT) and five GABAN-methyl-3,4-dihydrocarbylphenylethylamine kinds latroinsectotoxins (LIT) (α-ε) 4,5, whose ), etc.. Vassiklevski implied that, such small molecular weight is 131 KDa, 120 KDa, 120KDa, molecules play a role not only as neurotransmitters 140 KDa, 120 KDa, 110 KDa and 110 KDa, and neuromodulators in an insect, but also as an respectively 6. Polyamines neurotoxins could be antifeedant since they cause pain. Furthermore, these represented by Americas funnel web spider small molecules in spider toxins can also increase (Agelenpsis aperta Gertsch) venom toxin, vascular permeability 10. Category 2 means protein α-agatoxins family. There typical necrosis poisonous components possessing a molecular weight of 10 toxin such as brown recluse spider especially KDa or more, mainly indicates the aforementioned Loxosceles spp. can produce severe local skin polymer toxins and proteases. The third category necrosis 7. The mixed spider toxins, could be indicated the peptidic toxins with their molecular exampled by tarantula spider toxins and Clubiona weights between 1000 Dalton and 10 KDa, these spider toxins, which exhibit neurotoxic poisons and substances is most abundant in the spider toxin necrotic features. components, and occupies an important position on According to difference of chemical composition, the spider toxins' bio-actions. Neurotoxins is an spider toxins contain a variety of constituents mainly important part of these substances. As of 2009, 172 www.ijapbc.com IJAPBC – Vol. 4(1), Jan - Mar, 2015 ISSN: 2277 - 4688 statistics results shows that among all of the peptidic of the total category. toxins have been identified, 174 contains three Among various types of small molecules in the spider disulfide bonds, 128 containing four disulfide bonds, venom, the most thoroughly studied part is 53 containing five pairs of disulfide bonds, containing polyamines, especially the arylpolyamines. This 24 owns six pairs of disulfide bonds, 5 comprising article lists some typical spider polyamines for seven pairs of disulfide bonds or more. In addition, reference (Fig. 1). Table 1 lists some spider toxins only 16 peptidic toxins possess odd number of reported to possess medicinal activities 11-61. cysteine residues, which represent a small proportion Table 1. Comparison of some important spider toxins possessing medicinal activities. Spider species Toxin’s name Amino acid sequence Pharmaco- Molecular weight (Da) logical activity Latrodectus α-Latrotoxin EGEDLTLEEKAEICSELELQQKYVDIASNII Ca2+ ion channel 131.5K tredecimguttatus (α-LTX) 5 GDLSSLPIVGKIAGTIAAAAMTATHVASGR LDIEQTLLGCSDLPFDQIKEVLENRFNEIDR KLDSHSAALEEITKLVEKSISVVEKTRKQM NKRFDEVMKSIQDAKVSPIISKINNFARYFD TEKERIRGLKLNDYILKLEEPNGILLHFKES RTPTDDSLQAPLFSIIEEGYAVPKSIDDELAF KVLYALLYGTQTYVSVMFFLLEQYSFLAN HYYEKG α- EMSRADQCKLLAYTAVGYETVGNVAADIA Effective against 120K Latroinsectoto SIEGANLVAAPVAAGGHLGKGLTDAAMIA insects xin MDCSSIPFEEIKEILNKEFKEMGRKLDKNT 5 EALEHVSKLVSKTLSTVEKIRVEMREGFKL (α-LIT) VIETIENIATKEIVFDINKIVQYFNNERENIN SRQKEEFVAKLQEPAPGNFLLYLRNSRTSE SGTLYSLLFRIIDQELAIPNNAGDNNAIQAL YALFYGTETFISIMFYLVKQYSYLAEYHYQ KG δ-Latroin-secto DEEDGEMTLEERQAQCKAIEYSNSVFGMI Effective against 110K toxin (δ-LIT) 5 ADVANDIGSIPVIGEVVGIVTAPIAIVSHITS insects AGLDIASTALDCDDIPFDEIKEILEERFNEID RKLDKNTAALEEVSKLVSKTFVTVEKTRN EMNENFKLVLETIESKEIKSIVFKINDFKKF FEKERQRIKGLPKDRYVAKLLEQKGILGSL KEVREPSGNSLSSALNELLDKNNNYAIPKV VDDNKAFQALYALFYGTQTYAAVMEFLLE QHSYLADYYYQKG Agelenpsis aperta ω-Aga-IA 11-13 AKALPPGSVCDGNESDCKCYGKWHKCRC Acting on 7.5K PWKWHFTGEGPCTCEKGMKHTCITKLHCP voltage -gated NKAEWGLDW calcium channels (L-type in DRG) ω-Aga-IIA 12-14 GCIEIGGDCDGYQEKSYCQCCRNNGFCS Acting on 10K voltage -gated calcium channels (N-type in chick synaptosomes) ω-Aga-IIIA SCIDIGGDCDGEKDDCQCCRRNGYCSCYS Acting on 8.5K 11,12,14 LFGYLKSGCKCVVGTSAEFQGICRRKARQ voltage -gated CYNSDPDKCESHNKPKRR calcium channels (L-,P/Q-,R-, N-type in rat brain synaptosomes) 173 www.ijapbc.com IJAPBC – Vol. 4(1), Jan - Mar, 2015 ISSN: 2277 - 4688 ω-Aga-IVA KKKCIAKDYGRCKWGGTPCCRGRGCICSI Acting on 5220.39 12,14,15 MGTNCECKPRLIMEGLGLA voltage -gated calcium channels (P/Q-type and P-type currents in cerebellar Purkinje neurons) ω-Aga-IVB 15 EDNCIAEDYGKCTWGGTKCCRGRPCRCS P-type VCCC 5287.13 MIGYNCECTPRLIMEGLSFA blocker μ-Aga-I 16 ECVPENCHCRDWYDECCEGFYCSCRQPPK Induces 4264 CICRNNN-NH2 repetitive firing 16 of action μ-Aga-II ECATKNKRCADWAGPWCCDGLYCSCRSY potennials in 4137 PGCMCRPSS ventrolateral 16 muscles of μ-Aga-III ADCVGDGQRCADWAGPYCCSGYYCSCRS 4188 MPYCRCRSDS-NH2 Musca domestica μ-Aga-IV 16 ACVGENQQCADWAGPHCCDGYYCTCRYF 4199 PKCICRNNN-NH2 μ-Aga-V 16 ACVGENKQCADWAGPHCCDGYYCTCRYF 4199 PKCICRNNN-NH2 μ-Aga-VI 16 DCVGESQQCADWAGPHCCDGYYCTCRYF 4159 PKCICVNNN Hadronyche versuta ω-ACTX-Hv2a LLACLFGNGRCSSNRDCCELTPVCKRGSC VSCC in 4478 17-19 VSSGPGLVGGILGGIL neurons of honeybee (Insect voltage-gate calcium) ω-ACTX-Hv1a SPTCIPSGQPCPYNENCCSQSCTFKENENG Acting on 4050 18 NTVKRCD voltage -gated calcium channels (VSCC in abdominal ganglia
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