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Venomous animals on the earth have been found to be valuable resources for the development of therapeutics. Enzymatic and non-enzymatic proteins and peptides are the major components of animal venoms, many of which can target various ion channels, receptors, and membrane transporters. Compared to traditional small molecule drugs, natural proteins and peptides exhibit higher specificity and potency to their targets. In this review, we summarize the varieties and characteristics of toxins from a few representative venomous animals, and describe the components and applications of animal toxins as potential drug candidates in the treatment of human diseases, including cancer, neurodegenerative diseases, cardiovascular diseases, neuropathic pain, as well as autoimmune diseases. In the meantime, there are many obstacles to translate new toxin discovery to their clinical applications. The challenges, strategies, and perspectives in the development of the protein toxin-based drugs are discussed as well.
Adams DJ, Berecki G, (2013) Mechanisms of conotoxin inhibition of N-type (Ca(v)2.2) calcium channels.Biochim Biophys Acta 1828:1619-1628
Akondi KB, Muttenthaler M, Dutertre S, Kaas Q, Craik DJ, Lewis RJ, Alewood PF, (2014) Discovery, synthesis, and structure-activity relationships of conotoxins.Chem Rev 114:5815-5847
Awad K, Abushouk AI, AbdelKarim AH, Mohammed M, Negida A, Shalash AS, (2017) Bee venom for the treatment of Parkinson’s disease: how far is it possible?.Biomed Pharmacother 91:295-302
Calderon LA, Sobrinho JC, Zaqueo KD, de Moura AA, Grabner AN, Mazzi MV, Marcussi S, Nomizo A, Fernandes CF, Zuliani JP, Carvalho BM, da Silva SL, Stábeli RG, Soares AM, (2014) Antitumoral activity of snake venom proteins: new trends in cancer therapy.Biomed Res Int 2014:203639
Capon DJ, Chamow SM, Mordenti J, Marsters SA, Gregory T, Mitsuya H, Byrn RA, Lucas C, Wurm FM, Groopman JE, Broder S, Smith DH, (1989) Designing CD4 immunoadhesins for AIDS therapy.Nature 337:525-531
Chassagnon IR, McCarthy CA, Chin YK-Y, Pineda SS, Keramidas A, Mobli M, Pham V, De Silva TM, Lynch JW, Widdop RE, Rash LD, King GF, (2017) Potent neuroprotection after stroke afforded by a double-knot spider-venom peptide that inhibits acid-sensing ion channel 1a.Proc Natl Acad Sci 114(14):3750-3755
Chen X, Wang K, (2016) The fate of medications evaluated for ischemic stroke pharmacotherapy over the period 1995–2015.Acta Pharm Sin B 6:522-530
Choi H, Hwang JS, Lee DG, (2014) Identification of a novel antimicrobial peptide, scolopendin 1, derived from centipede Scolopendra subspinipes mutilans and its antifungal mechanism.Insect Mol Biol 23:788-799
Cizkova D, Marsala J, Lukacova N, Marsala M, Jergova S, Orendacova J, Yaksh TL, (2002) Localization of N-type Ca2+ channels in the rat spinal cord following chronic constrictive nerve injury.Exp Brain Res 147:456-463
Cohen-Inbar O, Zaaroor M, (2016) Glioblastoma multiforme targeted therapy: the Chlorotoxin story.J Clin Neurosci 33:52-58
Cristofori-Armstrong B, Rash LD, (2017) Acid-sensing ion channel (ASIC) structure and function: insights from spider, snake and sea anemone venoms.Neuropharmacology 127:173-184
de Souza JM, Goncalves BDC, Gomez MV, Vieira LB, Ribeiro FM, (2018) Animal toxins as therapeutic tools to treat neurodegenerative diseases.Front Pharmacol 9:145
Deuis JR, Dekan Z, Wingerd JS, Smith JJ, Munasinghe NR, Bhola RF, Imlach WL, Herzig V, Armstrong DA, Rosengren KJ, Bosmans F, Waxman SG, Dib-Hajj SD, Escoubas P, Minett MS, Christie MJ, King GF, Alewood PF, Lewis RJ, Wood JN, Vetter I, (2017) Pharmacological characterisation of the highly NaV1.7 selective spider venom peptide Pn3a.Sci Rep 7:40883
Deval E, Lingueglia E, (2015) Acid-sensing ion channels and nociception in the peripheral and central nervous systems.Neuropharmacology 94:49-57
Ding J, Chua P-J, Bay B-H, Gopalakrishnakone P, (2014) Scorpion venoms as a potential source of novel cancer therapeutic compounds.Exp Biol Med 239:387-393
Ding J, Chua PJ, Bay BH, Gopalakrishnakone P, (2014) Scorpion venoms as a potential source of novel cancer therapeutic compounds.Exp Biol Med (Maywood) 239:387-393
Edwards W, Fung-Leung WP, Huang C, Chi E, Wu N, Liu Y, Maher MP, Bonesteel R, Connor J, Fellows R, Garcia E, Lee J, Lu L, Ngo K, Scott B, Zhou H, Swanson RV, Wickenden AD, (2014) Targeting the ion channel KV1.3 with scorpion venom peptides engineered for potency, selectivity, and half-life.J Biol Chem 289:22704-22714
Fratini F, Cilia G, Turchi B, Felicioli A, (2017) Insects, arachnids and centipedes venom: a powerful weapon against bacteria. A literature review.Toxicon 130:91-103
Hakim MA, Yang SL, Lai R, (2015) Centipede venoms and their components: resources for potential therapeutic applications.Toxins 7:4832-4851
Hamad MK, He K, Abdulrazeq HF, Mustafa AM, Luceri R, Kamal N, Ali M, Nakhla J, Herzallah MM, Mammis A, (2018) Potential uses of isolated toxin peptides in neuropathic pain relief: a literature review.World Neurosurg 113(333–347):e335
Harrison PL, Abdel-Rahman MA, Miller K, Strong PN, (2014) Antimicrobial peptides from scorpion venoms.Toxicon 88:115-137
Jain D, Kumar S, (2012) Snake venom: a potent anticancer agent.Asian Pac J Cancer Prev 13:4855-4860
Lewis RJ, Garcia ML, (2003) Therapeutic potential of venom peptides.Nat Rev Drug Discov 2:790-802
Liu T, Liu Y, Wang Y, Hull M, Schultz PG, Wang F, (2014) Rational design of CXCR4 specific antibodies with elongated CDRs.J Am Chem Soc 136:10557-10560
Macedo JKA, Fox JW, de Souza Castro M, (2015) Disintegrins from snake venoms and their applications in cancer research and therapy.Curr Protein Pept Sci 16:532-548
Mahadevappa R, Ma R, Kwok HF, (2017) Venom peptides: improving specificity in cancer therapy.Trends Cancer 3:611-614
Masuyer G, Schwager SL, Sturrock ED, Isaac RE, Acharya KR, (2012) Molecular recognition and regulation of human angiotensin-I converting enzyme (ACE) activity by natural inhibitory peptides.Sci Rep 2:717
Matsui T, Fujimura Y, Titani K, (2000) Snake venom proteases affecting hemostasis and thrombosis.Biochim Biophys Acta 1477:146-156
Murray JK, Qian YX, Liu B, Elliott R, Aral J, Park C, Zhang X, Stenkilsson M, Salyers K, Rose M, Li H, Yu S, Andrews KL, Colombero A, Werner J, Gaida K, Sickmier EA, Miu P, Itano A, McGivern J, Gegg CV, Sullivan JK, Miranda LP, (2015) Pharmaceutical optimization of peptide toxins for ion channel targets: potent, selective, and long-lived antagonists of KV1.3.J Med Chem 58:6784-6802
Nalivaeva NN, Beckett C, Belyaev ND, Turner AJ, (2012) Are amyloid-degrading enzymes viable therapeutic targets in Alzheimer’s disease? J Neurochem 120(Suppl 1):167-185
Nielsen CK, Lewis RJ, Alewood D, Drinkwater R, Palant E, Patterson M, Yaksh TL, McCumber D, Smith MT, (2005) Anti-allodynic efficacy of the chi-conopeptide, Xen2174, in rats with neuropathic pain.Pain 118:112-124
Obata H, Conklin D, Eisenach JC, (2005) Spinal noradrenaline transporter inhibition by reboxetine and Xen2174 reduces tactile hypersensitivity after surgery in rats.Pain 113:271-276
Oršolić N, (2012) Bee venom in cancer therapy.Cancer Metastasis Rev 31:173-194
Pal SK, Gomes A, Dasgupta SC, Gomes A, (2002) Snake venom as therapeutic agents: from toxin to drug development.Indian J Exp Biol 40:1353-1358
Rigo FK, Dalmolin GD, Trevisan G, Tonello R, Silva MA, Rossato MF, Klafke JZ, Cordeiro MDN, Castro Junior CJ, Montijo D, Gomez MV, Ferreira J, (2013) Effect of ω-conotoxin MVIIA and Phα1β on paclitaxel-induced acute and chronic pain.Pharmacol Biochem Behav 114–115:16-22
Rodriguez C, Rollins-Smith L, Ibanez R, Durant-Archibold AA, Gutierrez M, (2017) Toxins and pharmacologically active compounds from species of the family Bufonidae (Amphibia, Anura).J Ethnopharmacol 198:235-254
Sahand ES, Shahla J, Delavar S, Pargol GM, Kamran PB, (2016) A new, high yield, rapid, and cost-effective protocol to deprotection of cysteine-rich conopeptide, omega-conotoxin MVIIA.Chem Biol Drug Des 87:687-693
Samy RP, Stiles BG, Franco OL, Sethi G, Lim LHK, (2017) Animal venoms as antimicrobial agents.Biochem Pharmacol 134:127-138
Scarborough RM, Rose JW, Hsu MA, Phillips DR, Fried VA, Campbell AM, Nannizzi L, Charo IF, (1991) Barbourin. A GPIIb-IIIa-specific integrin antagonist from the venom of Sistrurus m. barbouri.J Biol Chem 266:9359-9362
Sharpe IA, Palant E, Schroeder CI, Kaye DM, Adams DJ, Alewood PF, Lewis RJ, (2003) Inhibition of the norepinephrine transporter by the venom peptide chi-MrIA. Site of action, Na+ dependence, and structure-activity relationship.J Biol Chem 278:40317-40323
Shen B, Cao Z, Li W, Sabatier JM, Wu Y, (2017) Treating autoimmune disorders with venom-derived peptides.Expert Opin Biol Ther 17:1065-1075
Silva J, Monge-Fuentes V, Gomes F, Lopes K, Anjos L, Campos G, Arenas C, Biolchi A, Gonçalves J, Galante P, Campos L, Mortari M, (2015) Pharmacological alternatives for the treatment of neurodegenerative disorders: wasp and bee venoms and their components as new neuroactive tools.Toxins 7:3179
Vyas VK, Brahmbhatt K, Bhatt H, Parmar U, (2013) Therapeutic potential of snake venom in cancer therapy: current perspectives.Asian Pac J Trop Biomed 3:156-162
Wang X, Guo Z, (2015) Anti-gliomas effect of chlorotoxin-conjugated onconase at high dose.Cell Biochem Biophys 73:389-392
Wang S-Z, Qin Z-H, (2018) Anti-inflammatory and immune regulatory actions of Naja naja atra venom.Toxins 10:100
Wang RE, Wang Y, Zhang Y, Gabrelow C, Zhang Y, Chi V, Fu Q, Luo X, Wang D, Joseph S, Johnson K, Chatterjee AK, Wright TM, Nguyen-Tran VT, Teijaro J, Theofilopoulos AN, Schultz PG, Wang F, (2016) Rational design of a KV1.3 channel-blocking antibody as a selective immunosuppressant.Proc Natl Acad Sci USA 113:11501-11506
Wang Y, O’Bryant Z, Wang H, Huang Y, (2016) Regulating factors in acid-sensing ion channel 1a function.Neurochem Res 41:631-645
Yang S, Liu Z, Xiao Y, Li Y, Rong M, Liang S, Zhang Z, Yu H, King GF, Lai R, (2012) Chemical punch packed in venoms makes centipedes excellent predators.Mol Cell Proteomics 11:640-650
Yang S, Xiao Y, Kang D, Liu J, Li Y, Undheim EA, Klint JK, Rong M, Lai R, King GF, (2013) Discovery of a selective NaV1.7 inhibitor from centipede venom with analgesic efficacy exceeding morphine in rodent pain models.Proc Natl Acad Sci USA 110:17534-17539
Zeng WZ, Liu DS, Xu TL, (2014) Acid-sensing ion channels: trafficking and pathophysiology.Channels (Austin) 8:481-487
Zhang Y, Wang D, de Lichtervelde L, Sun SB, Smider VV, Schultz PG, Wang F, (2013) Functional antibody CDR3 fusion proteins with enhanced pharmacological properties.Angew Chem Int Ed Engl 52:8295-8298
Zhang Y, Wang D, Welzel G, Wang Y, Schultz PG, Wang F, (2013) An antibody CDR3-erythropoietin fusion protein.ACS Chem Biol 8:2117-2121
Zhang Y, Goswami D, Wang D, Wang TS, Sen S, Magliery TJ, Griffin PR, Wang F, Schultz PG, (2014) An antibody with a variable-region coiled-coil “knob” domain.Angew Chem Int Ed Engl 53:132-135
Zhao Y, Cai X, Ye T, Huo J, Liu C, Zhang S, Cao P, (2011) Analgesic-antitumor peptide inhibits proliferation and migration of SHG-44 human malignant glioma cells.J Cell Biochem 112:2424-2434
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