1932

Abstract

Snake venoms are primarily composed of proteins and peptides, and these toxins have developed high selectivity to their biological targets. This makes venoms interesting for exploration into protein evolution and structure–function relationships. A single venom protein superfamily can exhibit a variety of pharmacological effects; these variations in activity originate from differences in functional sites, domains, posttranslational modifications, and the formations of toxin complexes. In this review, we discuss examples of how the major venom protein superfamilies have diversified, as well as how newer technologies in the omics fields, such as genomics, transcriptomics, and proteomics, can be used to characterize both known and unknown toxins.Because toxins are bioactive molecules with a rich diversity of activities, they can be useful as therapeutic and diagnostic agents, and successful examples of toxin applications in these areas are also reviewed. With the current rapid pace of technology, snake venom research and its applications will only continue to expand.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-animal-021419-083626
2020-02-15
2024-04-19
Loading full text...

Full text loading...

/deliver/fulltext/animal/8/1/annurev-animal-021419-083626.html?itemId=/content/journals/10.1146/annurev-animal-021419-083626&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Gutiérrez JM, Calvete JJ, Habib AG, Harrison RA, Williams DJ, Warrell DA 2017. Snakebite envenoming. Nat. Rev. Dis. Prim. 3:17063
    [Google Scholar]
  2. 2. 
    Calvete JJ. 2014. Next-generation snake venomics: protein-locus resolution through venom proteome decomplexation. Expert Rev. Proteom. 11:315–29
    [Google Scholar]
  3. 3. 
    Calvete JJ, Sanz L, Angulo Y, Lomonte B, Gutiérrez JM 2009. Venoms, venomics, antivenomics. FEBS Lett 583:1736–43
    [Google Scholar]
  4. 4. 
    Tasoulis T, Isbister GK. 2017. A review and database of snake venom proteomes. Toxins 9:9290
    [Google Scholar]
  5. 5. 
    Brahma RK, McCleary RJR, Kini RM, Doley R 2015. Venom gland transcriptomics for identifying, cataloging, and characterizing venom proteins in snakes. Toxicon 93:1–10
    [Google Scholar]
  6. 6. 
    Fry BG, Vidal N, Norman JA, Vonk FJ, Scheib H et al. 2005. Early evolution of the venom system in lizards and snakes. Nature 439:584
    [Google Scholar]
  7. 7. 
    Uetz P, Freed P, Hosek J 2018. The Reptile Database http://www.reptile-database.org/
  8. 8. 
    Kochva E. 1987. The origin of snakes and evolution of the venom apparatus. Toxicon 25:65–106
    [Google Scholar]
  9. 9. 
    Pyron RA, Burbink FT, Wiens JJ 2013. A phylogeny and revised classification of Squamata, including 4161 species of lizards and snakes. BMC Evol. Biol. 13:93
    [Google Scholar]
  10. 10. 
    Vonk FJ, Admiraal JF, Jackson K, Reshef R, de Bakker MA et al. 2008. Evolutionary origin and development of snake fangs. Nature 454:630–33
    [Google Scholar]
  11. 11. 
    Jackson K. 2003. The evolution of venom-delivery systems in snakes. Zool. J. Linn. Soc. 137:337–54
    [Google Scholar]
  12. 12. 
    Weinstein SA, White J, Keyler DE, Warrell DA 2013. Non-front-fanged colubroid snakes: a current evidence-based analysis of medical significance. Toxicon 69:103–13
    [Google Scholar]
  13. 13. 
    Kardong KV. 2002. Colubrid snakes and Duvernoy's “venom” glands. J. Toxicol. Toxin Rev. 21:1–19
    [Google Scholar]
  14. 14. 
    Mackessy SP. 2010. Field of reptile toxinology: snakes, lizards, and their venoms. Handbook of Venoms and Toxins of Reptiles SP Mackessy 2–23 Boca Raton, FL: CRC Press/Taylor & Francis Group
    [Google Scholar]
  15. 15. 
    McGivern JJ, Wray KP, Margres MJ, Couch ME, Mackessy SP, Rokyta DR 2014. RNA-seq and high-definition mass spectrometry reveal the complex and divergent venoms of two rear-fanged colubrid snakes. BMC Genom 15:1061
    [Google Scholar]
  16. 16. 
    Pla D, Petras D, Saviola AJ, Modahl CM, Sanz L et al. 2017. Transcriptomics-guided bottom-up and top-down venomics of neonate and adult specimens of the arboreal rear-fanged Brown Treesnake, Boiga irregularis, from Guam. J. Proteom. 174:71–84
    [Google Scholar]
  17. 17. 
    Modahl CM, Mrinalini Frietze S, Mackessy SP 2018. Adaptive evolution of distinct prey-specific toxin genes in rear-fanged snake venom. Proc. Biol. Sci. 285:20181003
    [Google Scholar]
  18. 18. 
    Pawlak J, Mackessy SP, Fry BG, Bhatia M, Mourier G et al. 2006. Denmotoxin, a three-finger toxin from the colubrid snake Boiga dendrophila (mangrove catsnake) with bird-specific activity. J. Biol. Chem. 281:29030–41
    [Google Scholar]
  19. 19. 
    Pahari S, Mackessy SP, Kini RM 2007. The venom gland transcriptome of the Desert Massasauga Rattlesnake (Sistrurus catenatus edwardsii): towards an understanding of venom composition among advanced snakes (Superfamily Colubroidea). BMC Mol. Biol. 8:115
    [Google Scholar]
  20. 20. 
    Junqueira-de-Azevedo ILM, Ching ATC, Carvalho E, Faria F, Nishiyama MY et al. 2006. Lachesis muta (Viperidae) cDNAs reveal diverging pit viper molecules and scaffolds typical of cobra (Elapidae) venoms: implications for snake toxin repertoire evolution. Genetics 173:877–89
    [Google Scholar]
  21. 21. 
    Makarova YV, Kryukova EV, Shelukhina IV, Lebedev DS, Andreeva TV et al. 2018. The first recombinant viper three-finger toxins: inhibition of muscle and neuronal nicotinic acetylcholine receptors. Dokl Biochem. Biophys. 479:127–30
    [Google Scholar]
  22. 22. 
    Tsetlin V. 1999. Snake venom α-neurotoxins and other ‘three-finger’ proteins. Eur. J. Biochem. 264:281–86
    [Google Scholar]
  23. 23. 
    Utkin YN. 2013. Three-finger toxins, a deadly weapon of elapid venom—milestones of discovery. Toxicon 62:50–55
    [Google Scholar]
  24. 24. 
    Kini RM, Doley R. 2010. Structure, function and evolution of three-finger toxins: mini proteins with multiple targets. Toxicon 56:855–67
    [Google Scholar]
  25. 25. 
    Bourne Y, Talley TT, Hansen SB, Taylor P, Marchot P 2005. Crystal structure of a Cbtx-AChBP complex reveals essential interactions between snake α-neurotoxins and nicotinic receptors. EMBO J 24:1512–22
    [Google Scholar]
  26. 26. 
    Nirthanan S, Gwee MCE. 2004. Three-finger α-neurotoxins and the nicotinic acetylcholine receptor, forty years on. J. Pharmacol. Sci. 94:1–17
    [Google Scholar]
  27. 27. 
    Chang CC, Lee CY. 1963. Isolation of neurotoxins from the venom of Bungarus multicinctus and their modes of neuromuscular blocking action. Arch. Int. Pharmacodyn. Ther. 144:241–57
    [Google Scholar]
  28. 28. 
    Chung C, Wu BN, Yang CC, Chang LS 2002. Muscarinic toxin-like proteins from Taiwan banded krait (Bungarus multicinctus) venom: purification, characterization and gene organization. J. Biol. Chem. 383:1397–406
    [Google Scholar]
  29. 29. 
    Karlsson E, Jolkkonen M, Mulugeta E, Onali P, Adem A 2000. Snake toxins with high selectivity for subtypes of muscarinic acetylcholine receptors. Biochimie 82:793–806
    [Google Scholar]
  30. 30. 
    Rajagopalan N, Pung YF, Zhu YZ, Wong PT, Kumar PP, Kini RM 2007. β-Cardiotoxin: a new three-finger toxin from Ophiophagus hannah (king cobra) venom with beta-blocker activity. FASEB J 21:3685–95
    [Google Scholar]
  31. 31. 
    Rosso J-P, Schwarz JR, Diaz-Bustamante M, Céard B, Gutiérrez JM et al. 2015. MmTX1 and MmTX2 from coral snake venom potently modulate GABAA receptor activity. PNAS 112:E891–900
    [Google Scholar]
  32. 32. 
    Rivera-Torres IO, Jin TB, Cadene M, Chait BT, Poget SF 2016. Discovery and characterisation of a novel toxin from Dendroaspis angusticeps, named Tx7335, that activates the potassium channel KcsA. Sci. Rep. 6:23904
    [Google Scholar]
  33. 33. 
    Yang DC, Deuis JR, Dashevsky D, Dobson J, Jackson TNW et al. 2016. The snake with the scorpion's sting: novel three-finger toxin sodium channel activators from the venom of the long-glanded blue coral snake (Calliophis bivirgatus). Toxins 8:303
    [Google Scholar]
  34. 34. 
    de Weille JR, Schweitz H, Maes P, Tartar A, Lazdunski M 1991. Calciseptine, a peptide isolated from black mamba venom, is a specific blocker of the L-type calcium channel. PNAS 88:2437–40
    [Google Scholar]
  35. 35. 
    Kini RM, Haar NC, Evans HJ 1988. Non-enzymatic inhibitors of coagulation and platelet aggregation from Naja nigricollis venom are cardiotoxins. Biochem. Biophys. Res. Commun. 150:1012–16
    [Google Scholar]
  36. 36. 
    Banerjee Y, Mizuguchi J, Iwanaga S, Kini RM 2005. Hemextin AB complex, a unique anticoagulant protein complex from Hemachatus haemachatus (African Ringhals cobra) venom that inhibits clot initiation and factor VIIa activity. J. Biol. Chem. 280:42601–11
    [Google Scholar]
  37. 37. 
    McDowell RS, Dennis MS, Louie A, Shuster M, Mulkerrin MG, Lazarus RA 1992. Mambin, a potent glycoprotein IIb-IIIa antagonist and platelet aggregation inhibitor structurally related to the short neurotoxins. Biochemistry 31:4766–72
    [Google Scholar]
  38. 38. 
    Servent D, Winckler-Dietrich V, Hu HY, Kessler P, Drevet P et al. 1997. Only snake curaremimetic toxins with a fifth disulfide bond have high affinity for the neuronal α7 nicotinic receptor. J. Biol. Chem. 272:24279–86
    [Google Scholar]
  39. 39. 
    Mordvintsev DY, Polyak YL, Rodionov DI, Jakubik J, Dolezal V et al. 2009. Weak toxin WTX from Naja kaouthia cobra venom interacts with both nicotinic and muscarinic acetylcholine receptors. FEBS J 276:5065–75
    [Google Scholar]
  40. 40. 
    Mordvintsev DY, Rodionov DI, Makarova MV, Kamensky AA, Levitskaya NG et al. 2007. Behavioural effects in mice and intoxication symptomatology of weak neurotoxin from cobra Naja kaouthia. Basic Clin. Pharmacol. Toxicol 100:273–78
    [Google Scholar]
  41. 41. 
    Pawlak J, Mackessy SP, Sixberry NM, Stura EA, Le Du MH et al. 2009. Irditoxin, a novel covalently linked heterodimeric three-finger toxin with high taxon-specific neurotoxicity. FASEB J 23:534–45
    [Google Scholar]
  42. 42. 
    Chiappinelli VA, Weaver WR, McLane KE, Conti-Fine BM, Fiordalisi JJ, Grant GA 1996. Binding of native κ-neurotoxins and site-directed mutants to nicotinic acetylcholine receptors. Toxicon 34:1243–56
    [Google Scholar]
  43. 43. 
    Roy A, Zhou X, Chong MZ, D'Hoedt D, Foo CS et al. 2010. Structural and functional characterization of a novel homodimeric three-finger neurotoxin from the venom of Ophiophagus hannah (king cobra). J. Biol. Chem. 285:8302–15
    [Google Scholar]
  44. 44. 
    Antil S, Servent D, Menez A 1999. Variability among the sites by which curaremimetic toxins bind to torpedo acetylcholine receptor, as revealed by identification of the functional residues of α-cobratoxin. J. Biol. Chem. 274:34851–58
    [Google Scholar]
  45. 45. 
    Antil-Delbeke S, Gaillard C, Tamiya T, Corringer PJ, Changeux JP et al. 2000. Molecular determinants by which a long chain toxin from snake venom interacts with the neuronal α7-nicotinic acetylcholine receptor. J. Biol. Chem. 275:29594–601
    [Google Scholar]
  46. 46. 
    Hassan-Puttaswamy V, Adams DJ, Kini RM 2015. A distinct functional site in Ω-neurotoxins: novel antagonists of nicotinic acetylcholine receptors from snake venom. ACS Chem. Biol. 10:2805–15
    [Google Scholar]
  47. 47. 
    Fox JW, Serrano SM. 2010. Snake venom metalloproteinases. Handbook of Venoms and Toxins of Reptiles SP Mackessy 95–114 Boca Raton, FL: CRC Press/Taylor & Francis Group
    [Google Scholar]
  48. 48. 
    Takeda S, Takeya H, Iwanaga S 2012. Snake venom metalloproteinases: structure, function and relevance to the mammalian ADAM/ADAMTS family proteins. Biochim. Biophys. Acta 1824:164–76
    [Google Scholar]
  49. 49. 
    Fox JW, Serrano SM. 2005. Structural considerations of the snake venom metalloproteinases, key members of the M12 reprolysin family of metalloproteinases. Toxicon 45:969–85
    [Google Scholar]
  50. 50. 
    Casewell NR, Wagstaff SC, Harrison RA, Renjifo C, Wuster W 2011. Domain loss facilitates accelerated evolution and neofunctionalization of duplicate snake venom metalloproteinase toxin genes. Mol. Biol. Evol. 28:2637–49
    [Google Scholar]
  51. 51. 
    Kini RM, Evans HJ. 1992. Structural domains in venom proteins: evidence that metalloproteinases and nonenzymatic platelet aggregation inhibitors (disintegrins) from snake venoms are derived by proteolysis from a common precursor. Toxicon 30:265–93
    [Google Scholar]
  52. 52. 
    Calvete JJ, Marcinkiewicz C, Monleón D, Esteve V, Celda B et al. 2005. Snake venom disintegrins: evolution of structure and function. Toxicon 45:1063–74
    [Google Scholar]
  53. 53. 
    Saviola AJ, Chiszar D, Busch C, Mackessy SP 2013. Molecular basis for prey relocation in viperid snakes. BMC Biol 11:20
    [Google Scholar]
  54. 54. 
    Moura-da-Silva AM, Almeida MT, Portes-Junior JA, Nicolau CA, Gomes-Neto F, Valente RH 2016. Processing of snake venom metalloproteinases: generation of toxin diversity and enzyme inactivation. Toxins 8:6E183
    [Google Scholar]
  55. 55. 
    Ohler M, Georgieva D, Seifert J, von Bergen M, Arni RK et al. 2010. The venomics of Bothrops alternatus is a pool of acidic proteins with predominant hemorrhagic and coagulopathic activities. J. Proteome Res. 9:2422–37
    [Google Scholar]
  56. 56. 
    Braud S, Bon C, Wisner A 2000. Snake venom proteins acting on hemostasis. Biochimie 82:851–59
    [Google Scholar]
  57. 57. 
    Kini RM. 2005. Serine proteases affecting blood coagulation and fibrinolysis from snake venoms. Pathophysiol. Haemost. Thromb. 34:200–4
    [Google Scholar]
  58. 58. 
    Serrano SM, Maroun RC. 2005. Snake venom serine proteinases: sequence homology versus substrate specificity, a paradox to be solved. Toxicon 45:1115–32
    [Google Scholar]
  59. 59. 
    Serrano SM. 2013. The long road of research on snake venom serine proteinases. Toxicon 62:19–26
    [Google Scholar]
  60. 60. 
    Ullah A, Masood R, Ali I, Ullah K, Ali H et al. 2018. Thrombin-like enzymes from snake venom: structural characterization and mechanism of action. Int. J. Biol. Macromol. 114:788–811
    [Google Scholar]
  61. 61. 
    Soares SG, Oliveira LL. 2009. Venom-sweet-venom: N-linked glycosylation in snake venom toxins. Protein Pept. Lett. 16:913–19
    [Google Scholar]
  62. 62. 
    García LT, Parreiras e Silva LT, Ramos OH, Carmona AK, Bersanetti PA, Selistre-de-Araujo HS 2004. The effect of post-translational modifications on the hemorrhagic activity of snake venom metalloproteinases. Comp. Biochem. Physiol. C Toxicol. Pharmacol. 138:23–32
    [Google Scholar]
  63. 63. 
    Hill RE, Mackessy SP. 2000. Characterization of venom (Duvernoy's secretion) from twelve species of colubrid snakes and partial sequence of four venom proteins. Toxicon 38:1663–87
    [Google Scholar]
  64. 64. 
    Kini RM. 1997. Venom Phospholipase A2 Enyzmes: Structure, Function and Mechanism Chichester, UK: John Wiley and Sons Ltd.
  65. 65. 
    Kini RM. 2003. Excitement ahead: structure, function and mechanism of snake venom phospholipase A2 enzymes. Toxicon 42:827–40
    [Google Scholar]
  66. 66. 
    Doley R, Kini RM. 2009. Protein complexes in snake venom. Cell. Mol. Life Sci. 66:2851–71
    [Google Scholar]
  67. 67. 
    Abe T, Alema S, Miledi R 1977. Isolation and characterization of presynaptically acting neurotoxins from the venom of Bungarus snakes. Eur. J. Biochem. 80:1–12
    [Google Scholar]
  68. 68. 
    Kwong PD, McDonald NQ, Sigler PB, Hendrickson WA 1995. Structure of β2-bungarotoxin: potassium channel binding by Kunitz modules and targeted phospholipase action. Structure 3:1109–19
    [Google Scholar]
  69. 69. 
    Tchorbanov B, Grishin E, Aleksiev B, Ovchinnikov Y 1978. A neurotoxic complex from the venom of the Bulgarian viper (Vipera ammodytes ammodytes) and a partial amino acid sequence of the toxic phospholipase A2. Toxicon 16:37–44
    [Google Scholar]
  70. 70. 
    Santos KF, Murakami MT, Cintra ACO, Toyama MH, Marangoni S et al. 2007. Crystallization and preliminary X-ray crystallographic analysis of the heterodimeric crotoxin complex and the isolated subunits crotapotin and phospholipase A2. Acta Crystallogr. F Struct. Biol. Cryst. Commun. 63:287–90
    [Google Scholar]
  71. 71. 
    Aird SD, Kaiser II, Lewis RV, Kruggel WG 1985. Rattlesnake presynaptic neurotoxins: primary structure and evolutionary origin of the acidic subunit. Biochemistry 24:7054–58
    [Google Scholar]
  72. 72. 
    Bon C, Changeux JP, Jeng TW, Fraenkel-Conrat H 1979. Postsynaptic effects of crotoxin and of its isolated subunits. Eur. J. Biochem. 99:471–81
    [Google Scholar]
  73. 73. 
    Kaiser II, Aird SD. 1987. A crotoxin homolog from the venom of the Uracoan rattlesnake (Crotalus vegrandis). Toxicon 25:1113–20
    [Google Scholar]
  74. 74. 
    Chen YH, Wang YM, Hseu MJ, Tsai IH 2004. Molecular evolution and structure-function relationships of crotoxin-like and asparagine-6-containing phospholipases A2 in pit viper venoms. Biochem. J. 381:25–34
    [Google Scholar]
  75. 75. 
    Pool WR, Bieber AL. 1981. Fractionation of midget faded rattlesnake (Crotalus viridis concolor) venom: lethal fractions and enzymatic activities. Toxicon 19:517–27
    [Google Scholar]
  76. 76. 
    French WJ, Hayes WK, Bush SP, Cardwell MD, Bader JO, Rael ED 2004. Mojave toxin in venom of Crotalus helleri (Southern Pacific Rattlesnake): molecular and geographic characterization. Toxicon 44:781–91
    [Google Scholar]
  77. 77. 
    Ho CL, Lee CY. 1981. Presynaptic actions of Mojave toxin isolated from Mojave rattlesnake (Crotalus scutulatus) venom. Toxicon 19:889–92
    [Google Scholar]
  78. 78. 
    Weinstein SA, Minton SA, Wilde CE 1985. The distribution among ophidian venoms of a toxin isolated from the venom of the Mojave rattlesnake (Crotalus scutulatus scutulatus). Toxicon 23:825–44
    [Google Scholar]
  79. 79. 
    Powell RL, Lieb CS, Rael ED 2004. Identification of a neurotoxic venom component in the tiger rattlesnake, Crotalus tigris. J. Herpetol. 38:1149–52
    [Google Scholar]
  80. 80. 
    Fohlman J, Lind P, Eaker D 1977. Taipoxin, an extremely potent presynaptic snake venom neurotoxin. Elucidation of the primary structure of the acidic carbohydrate-containing taipoxin-subunit, a prophospholipase homolog. FEBS Lett 84:367–71
    [Google Scholar]
  81. 81. 
    Pearson JA, Tyler MI, Retson KV, Howden MEH 1991. Studies on the subunit structure of textilotoxin, a potent presynaptic neurotoxin from the venom of the Australian common brown snake (Pseudonaja textilis). 2. The amino acid sequence and toxicity studies of subunit D. Biochim. Biophys. Acta 1077:147–50
    [Google Scholar]
  82. 82. 
    Su MJ, Coulter AR, Sutherland SK, Chang CC 1983. The presynaptic neuromuscular blocking effect and phospholipase A2 activity of textilotoxin, a potent toxin isolated from the venom of the Australian brown snake, Pseudonaja textilis. Toxicon 21:143–51
    [Google Scholar]
  83. 83. 
    Boldrini-França J, Cologna CT, Pucca MB, Bordon KC, Amorim FG et al. 2017. Minor snake venom proteins: structure, function and potential applications. Biochim. Biophys. Acta 1861:824–38
    [Google Scholar]
  84. 84. 
    Fonslow BR, Kang SA, Gestaut DR, Graczyk B, Davis TN et al. 2010. Native capillary isoelectric focusing for the separation of protein complex isoforms and subcomplexes. Anal. Chem. 82:6643–51
    [Google Scholar]
  85. 85. 
    Tran JC, Zamdborg L, Ahlf DR, Lee JE, Catherman AD et al. 2011. Mapping intact protein isoforms in discovery mode using top-down proteomics. Nature 480:254–58
    [Google Scholar]
  86. 86. 
    Zhou Y, Zhang X, Fornelli L, Compton PD, Kelleher N, Wirth MJ 2017. Chromatographic efficiency and selectivity in top-down proteomics of histones. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 1044–45:47–53
    [Google Scholar]
  87. 87. 
    Capriotti AL, Cavaliere C, Foglia P, Samperi R, Lagana A 2011. Intact protein separation by chromatographic and/or electrophoretic techniques for top-down proteomics. J. Chromatogr. A 1218:8760–76
    [Google Scholar]
  88. 88. 
    Chapeaurouge A, Silva A, Carvalho P, McCleary RJR, Modahl CM et al. 2018. Proteomic deep mining the venom of the red-headed krait, Bungarus flaviceps. Toxins 10:9373
    [Google Scholar]
  89. 89. 
    Calvete JJ. 2013. Snake venomics: from the inventory of toxins to biology. Toxicon 75:44–62
    [Google Scholar]
  90. 90. 
    Calvete JJ. 2012. Venomics, what else?. Toxicon 60:427–33
    [Google Scholar]
  91. 91. 
    Escoubas P, Quinton L, Nicholson GM 2008. Venomics: unravelling the complexity of animal venoms with mass spectrometry. J. Mass Spectrom. 43:3279–95
    [Google Scholar]
  92. 92. 
    Fox JW, Serrano SM. 2008. Exploring snake venom proteomes: multifaceted analyses for complex toxin mixtures. Proteomics 8:909–20
    [Google Scholar]
  93. 93. 
    Serrano SM, Shannon JD, Wang D, Camargo AC, Fox JW 2005. A multifaceted analysis of viperid snake venoms by two-dimensional gel electrophoresis: an approach to understanding venom proteomics. Proteomics 5:501–10
    [Google Scholar]
  94. 94. 
    Sousa LF, Nicolau CA, Peixoto PS, Bernardoni JL, Oliveira SS et al. 2013. Comparison of phylogeny, venom composition and neutralization by antivenom in diverse species of Bothrops complex. PLOS Negl. Trop. Dis. 7:e2442
    [Google Scholar]
  95. 95. 
    Melani RD, Nogueira FCS, Domont GB 2017. It is time for top-down venomics. J. Venom. Anim. Toxins Incl. Trop. Dis. 23:44
    [Google Scholar]
  96. 96. 
    Melani RD, Skinner OS, Fornelli L, Domont GB, Compton PD, Kelleher NL 2016. Mapping proteoforms and protein complexes from king cobra venom using both denaturing and native top-down proteomics. Mol. Cell. Proteom. 15:2423–34
    [Google Scholar]
  97. 97. 
    Choudhury M, McCleary RJR, Kesherwani M, Kini RM, Velmurugan D 2017. Comparison of proteomic profiles of the venoms of two of the ‘Big Four’ snakes of India, the Indian cobra (Naja naja) and the common krait (Bungarus caeruleus), and analyses of their toxins. Toxicon 135:33–42
    [Google Scholar]
  98. 98. 
    Petras D, Heiss P, Sussmuth RD, Calvete JJ 2015. Venom proteomics of Indonesian king cobra, Ophiophagus hannah: integrating top-down and bottom-up approaches. J. Proteome Res. 14:2539–56
    [Google Scholar]
  99. 99. 
    Vandenplas ML, Vandenplas S, Brebner K, Bester AJ, Boyd CD 1985. Characterization of the messenger RNA population coding for components of viperid snake venom. Toxicon 23:289–305
    [Google Scholar]
  100. 100. 
    Junqueira de Azevedo IL, Farsky SH, Oliveira ML, Ho PL 2001. Molecular cloning and expression of a functional snake venom vascular endothelium growth factor (VEGF) from the Bothrops insularis pit viper: a new member of the VEGF family of proteins. J. Biol. Chem. 276:39836–42
    [Google Scholar]
  101. 101. 
    Leonardi A, Sajevic T, Pungerčar J, Križaj I 2019. Comprehensive study of the proteome and transcriptome of the venom of the most venomous European viper: discovery of a new subclass of ancestral snake venom metalloproteinase precursor-derived proteins. J. Proteome Res. 18:2287–309
    [Google Scholar]
  102. 102. 
    Rokyta DR, Wray KP, Lemmon AR, Lemmon EM, Caudle BS 2011. A high-throughput venom-gland transcriptome for the Eastern Diamondback Rattlesnake (Crotalus adamanteus) and evidence for pervasive positive selection across toxin classes. Toxicon 57:657–71
    [Google Scholar]
  103. 103. 
    Campos PF, Andrade-Silva D, Zelanis A, Paes Leme AF, Rocha MM et al. 2016. Trends in the evolution of snake toxins underscored by an integrative omics approach to profile the venom of the colubrid Phalotris mertensi. Genome Biol. Evol 8:2266–87
    [Google Scholar]
  104. 104. 
    Lowe R, Shirley N, Bleackley M, Dolan S, Shafee T 2017. Transcriptomics technologies. PLOS Comput. Biol. 13:e1005457
    [Google Scholar]
  105. 105. 
    Wang Z, Gerstein M, Snyder M 2009. RNA-Seq: a revolutionary tool for transcriptomics. Nat. Rev. Genet. 10:57–63
    [Google Scholar]
  106. 106. 
    Liu L, Li Y, Li S, Hu N, He Y et al. 2012. Comparison of next-generation sequencing systems. J. Biomed. Biotechnol. 2012:251364
    [Google Scholar]
  107. 107. 
    Hofmann EP, Rautsaw RM, Strickland JL, Holding ML, Hogan MP et al. 2018. Comparative venom-gland transcriptomics and venom proteomics of four Sidewinder Rattlesnake (Crotalus cerastes) lineages reveal little differential expression despite individual variation. Sci. Rep. 8:15534
    [Google Scholar]
  108. 108. 
    Aird SD, da Silva NJ, Qiu L, Villar-Briones A, Saddi VA et al. 2017. Coralsnake venomics: analyses of venom gland transcriptomes and proteomes of six Brazilian taxa. Toxins 9:6187
    [Google Scholar]
  109. 109. 
    Dashevsky D, Debono J, Rokyta D, Nouwens A, Josh P, Fry BG 2018. Three-finger toxin diversification in the venoms of cat-eye snakes (Colubridae: Boiga). J. Mol. Evol. 86:8531–545
    [Google Scholar]
  110. 110. 
    Holding ML, Margres MJ, Mason AJ, Parkinson CL, Rokyta DR 2018. Evaluating the performance of de novo assembly methods for venom-gland transcriptomics. Toxins 10:6249
    [Google Scholar]
  111. 111. 
    Jackson TNW, Sunagar K, Undheim EAB, Koludarov I, Chan AHC et al. 2013. Venom down under: dynamic evolution of Australian elapid snake toxins. Toxins 5:2621–55
    [Google Scholar]
  112. 112. 
    Ainsworth S, Petras D, Engmark M, Sussmuth RD, Whiteley G et al. 2018. The medical threat of mamba envenoming in sub-Saharan Africa revealed by genus-wide analysis of venom composition, toxicity and antivenomics profiling of available antivenoms. J. Proteom. 172:173–89
    [Google Scholar]
  113. 113. 
    Durban J, Sasa M, Calvete JJ 2018. Venom gland transcriptomics and microRNA profiling of juvenile and adult yellow-bellied sea snake, Hydrophis platurus, from Playa del Coco (Guanacaste, Costa Rica). Toxicon 153:96–105
    [Google Scholar]
  114. 114. 
    Margres M, Aronow K, Loyacano J, Rokyta D 2013. The venom-gland transcriptome of the eastern coral snake (Micrurus fulvius) reveals high venom complexity in the intragenomic evolution of venoms. BMC Genom 14:1–18
    [Google Scholar]
  115. 115. 
    Xu N, Zhao HY, Yin Y, Shen SS, Shan LL et al. 2017. Combined venomics, antivenomics and venom gland transcriptome analysis of the monocoled cobra (Naja kaouthia) from China. J. Proteom. 159:19–31
    [Google Scholar]
  116. 116. 
    Tan KY, Tan CH, Chanhome L, Tan NH 2017. Comparative venom gland transcriptomics of Naja kaouthia (monocled cobra) from Malaysia and Thailand: elucidating geographical venom variation and insights into sequence novelty. PeerJ 5:e3142
    [Google Scholar]
  117. 117. 
    Tan CH, Tan KY, Fung SY, Tan NH 2015. Venom-gland transcriptome and venom proteome of the Malaysian king cobra (Ophiophagus hannah). BMC Genom 16:687
    [Google Scholar]
  118. 118. 
    Vonk FJ, Casewell NR, Henkel CV, Heimberg AM, Jansen HJ et al. 2013. The king cobra genome reveals dynamic gene evolution and adaptation in the snake venom system. PNAS 110:20651–56
    [Google Scholar]
  119. 119. 
    Reeks T, Lavergne V, Sunagar K, Jones A, Undheim E et al. 2016. Deep venomics of the Pseudonaja genus reveals inter- and intra-specific variation. J. Proteom. 133:20–32
    [Google Scholar]
  120. 120. 
    Durban J, Juárez P, Angulo Y, Lomonte B, Flores-Diaz M et al. 2011. Profiling the venom gland transcriptomes of Costa Rican snakes by 454 pyrosequencing. BMC Genom 12:259
    [Google Scholar]
  121. 121. 
    Amazonas DR, Portes-Junior JA, Nishiyama-Jr MY, Nicolau CA, Chalkidis HM et al. 2018. Molecular mechanisms underlying intraspecific variation in snake venom. J. Proteom. 181:60–72
    [Google Scholar]
  122. 122. 
    Junqueira-de-Azevedo ILM, Bastos CMV, Ho PL, Luna MS, Yamanouye N, Casewell NR 2015. Venom-related transcripts from Bothrops jararaca tissues provide novel molecular insights into the production and evolution of snake venom. Mol. Biol. Evol. 32:754–66
    [Google Scholar]
  123. 123. 
    Rokyta DR, Lemmon AR, Margres MJ, Aronow K 2012. The venom-gland transcriptome of the eastern diamondback rattlesnake (Crotalus adamanteus). BMC Genom 13:312
    [Google Scholar]
  124. 124. 
    Wiezel GA, Shibao PYT, Cologna CT, Morandi Filho R, Ueira-Vieira C et al. 2018. In-depth venome of the Brazilian rattlesnake Crotalus durissus terrificus: an integrative approach combining its venom gland transcriptome and venom proteome. J. Proteome Res. 17:3941–58
    [Google Scholar]
  125. 125. 
    Rokyta DR, Wray KP, Margres MJ 2013. The genesis of an exceptionally lethal venom in the timber rattlesnake (Crotalus horridus) revealed through comparative venom-gland transcriptomics. BMC Genom 14:394
    [Google Scholar]
  126. 126. 
    Sunagar K, Undheim EA, Scheib H, Gren EC, Cochran C et al. 2014. Intraspecific venom variation in the medically significant Southern Pacific Rattlesnake (Crotalus oreganus helleri): biodiscovery, clinical and evolutionary implications. J. Proteom. 99:68–83
    [Google Scholar]
  127. 127. 
    Strickland JL, Mason AJ, Rokyta DR, Parkinson CL 2018. Phenotypic variation in Mojave rattlesnake (Crotalus scutulatus) venom is driven by four toxin families. Toxins 10:4135
    [Google Scholar]
  128. 128. 
    Durban J, Sanz L, Trevisan-Silva D, Neri-Castro E, Alagon A, Calvete JJ 2017. Integrated venomics and venom gland transcriptome analysis of juvenile and adult Mexican rattlesnakes Crotalus simus, C. tzabcan, and C. culminatus revealed miRNA-modulated ontogenetic shifts. J. Proteome Res. 16:3370–90
    [Google Scholar]
  129. 129. 
    Yee KT, Tongsima S, Ngamohiw C, Vasieva O, Rojnuckarin P 2019. Analysis of snake venom metalloproteinases from Myanmar Russell's viper transcriptome. Toxicon 158:S46–S47
    [Google Scholar]
  130. 130. 
    Hargreaves AD, Mulley JF. 2015. Assessing the utility of the Oxford Nanopore MinION for snake venom gland cDNA sequencing. PeerJ 3:e1441
    [Google Scholar]
  131. 131. 
    Aird SD, Watanabe Y, Villar-Briones A, Roy MC, Terada K, Mikheyev AS 2013. Quantitative high-throughput profiling of snake venom gland transcriptomes and proteomes (Ovophis okinavensis and Protobothrops flavoviridis). BMC Genom 14:790
    [Google Scholar]
  132. 132. 
    Pla D, Sanz L, Whiteley G, Wagstaff SC, Harrison RA et al. 2017. What killed Karl Patterson Schmidt? Combined venom gland transcriptomic, venomic and antivenomic analysis of the South African green tree snake (the boomslang), Dispholidus typus. Biochim. Biophys. Acta 1861:814–23
    [Google Scholar]
  133. 133. 
    Junqueira-de-Azevedo IL, Campos PF, Ching AT, Mackessy SP 2016. Colubrid venom composition: an -omics perspective. Toxins 8:E230
    [Google Scholar]
  134. 134. 
    Zhang Z, Zhang X, Hu T, Zhou W, Cui Q et al. 2015. Discovery of toxin-encoding genes from the false viper Macropisthodon rudis, a rear-fanged snake, by transcriptome analysis of venom gland. Toxicon 106:72–78
    [Google Scholar]
  135. 135. 
    Brust A, Sunagar K, Undheim EA, Vetter I, Yang DC et al. 2013. Differential evolution and neofunctionalization of snake venom metalloprotease domains. Mol. Cell. Proteom. 12:651–63
    [Google Scholar]
  136. 136. 
    Terrat Y, Sunagar K, Fry BG, Jackson TNW, Scheib H et al. 2013. Atractaspis aterrima toxins: the first insight into the molecular evolution of venom in side-stabbers. Toxins 5:1948–64
    [Google Scholar]
  137. 137. 
    O'Neil ST, Emrich SJ. 2013. Assessing de novo transcriptome assembly metrics for consistency and utility. BMC Genom 14:465
    [Google Scholar]
  138. 138. 
    Modahl CM, Frietze S, Mackessy SP 2018. Transcriptome-facilitated proteomic characterization of rear-fanged snake venoms reveal abundant metalloproteinases with enhanced activity. J. Proteom. 187:223–34
    [Google Scholar]
  139. 139. 
    Andrade-Silva D, Zelanis A, Kitano ES, Junqueira-de-Azevedo IL, Reis MS et al. 2016. Proteomic and glycoproteomic profilings reveal that post-translational modifications of toxins contribute to venom phenotype in snakes. J. Proteome Res. 15:2658–75
    [Google Scholar]
  140. 140. 
    Degueldre M, Echterbille J, Smargiasso N, Damblon C, Gouin C et al. 2017. In-depth glyco-peptidomics approach reveals unexpected diversity of glycosylated peptides and atypical post-translational modifications in Dendroaspis angusticeps snake venom. Int. J. Mol. Sci. 18:2453
    [Google Scholar]
  141. 141. 
    Castoe TA, de Koning APJ, Hall KT, Card DC, Schield DR et al. 2013. The Burmese python genome reveals the molecular basis for extreme adaptation in snakes. PNAS 110:20645–50
    [Google Scholar]
  142. 142. 
    Bradnam KR, Fass JN, Alexandrov A, Baranay P, Bechner M et al. 2013. Assemblathon 2: evaluating de novo methods of genome assembly in three vertebrate species. GigaScience 2:2047–217X-2-10
    [Google Scholar]
  143. 143. 
    Gilbert C, Meik JM, Dashevsky D, Card DC, Castoe TA, Schaack S 2014. Endogenous hepadnaviruses, bornaviruses and circoviruses in snakes. Proc. Biol. Sci. 281:20141122
    [Google Scholar]
  144. 144. 
    Ullate-Agote A, Milinkovitch MC, Tzika AC 2014. The genome sequence of the corn snake (Pantherophis guttatus), a valuable resource for EvoDevo studies in squamates. Int. J. Dev. Biol. 58:881–88
    [Google Scholar]
  145. 145. 
    Yin W, Wang Z-j, Li Q-y, Lian J-m, Zhou Y et al. 2016. Evolutionary trajectories of snake genes and genomes revealed by comparative analyses of five-pacer viper. Nat. Commun. 7:13107
    [Google Scholar]
  146. 146. 
    Aird SD, Arora J, Barua A, Qiu L, Terada K, Mikheyev AS 2017. Population genomic analysis of a pitviper reveals microevolutionary forces underlying venom chemistry. Genome Biol. Evol. 9:2640–49
    [Google Scholar]
  147. 147. 
    Shibata H, Chijiwa T, Oda-Ueda N, Nakamura H, Yamaguchi K et al. 2018. The habu genome reveals accelerated evolution of venom protein genes. Sci. Rep. 8:11300
    [Google Scholar]
  148. 148. 
    Perry BW, Card DC, McGlothlin JW, Pasquesi GIM, Adams RH et al. 2018. Molecular adaptations for sensing and securing prey and insight into amniote genome diversity from the garter snake genome. Genome Biol. Evol. 10:2110–29
    [Google Scholar]
  149. 149. 
    Schield DR, Card DC, Hales NR, Perry BW, Pasquesi GM et al. 2019. The origins and evolution of chromosomes, dosage compensation, and mechanisms underlying venom regulation in snakes. Genome Res 29:590–601
    [Google Scholar]
  150. 150. 
    Li J-T, Gao Y-D, Xie L, Deng C, Shi P et al. 2018. Comparative genomic investigation of high-elevation adaptation in ectothermic snakes. PNAS 115:8406
    [Google Scholar]
  151. 151. 
    Vicoso B, Emerson JJ, Zektser Y, Mahajan S, Bachtrog D 2013. Comparative sex chromosome genomics in snakes: differentiation, evolutionary strata, and lack of global dosage compensation. PLOS Biol 11:e1001643
    [Google Scholar]
  152. 152. 
    Pasquesi GIM, Adams RH, Card DC, Schield DR, Corbin AB et al. 2018. Squamate reptiles challenge paradigms of genomic repeat element evolution set by birds and mammals. Nat. Commun. 9:2774
    [Google Scholar]
  153. 153. 
    Castoe TA, Hall KT, Guibotsy Mboulas ML, Gu W, de Koning APJ et al. 2011. Discovery of highly divergent repeat landscapes in snake genomes using high-throughput sequencing. Genome Biol. Evol. 3:641–53
    [Google Scholar]
  154. 154. 
    Juárez P, Comas I, González-Candelas F, Calvete JJ 2008. Evolution of snake venom disintegrins by positive Darwinian selection. Mol. Biol. Evol. 25:2391–407
    [Google Scholar]
  155. 155. 
    Deshimaru M, Ogawa T, Nakashima K, Nobuhisa I, Chijiwa T et al. 1996. Accelerated evolution of crotalinae snake venom gland serine proteases. FEBS Lett 397:83–88
    [Google Scholar]
  156. 156. 
    Aird SD, Aggarwal S, Villar-Briones A, Tin MM, Terada K, Mikheyev AS 2015. Snake venoms are integrated systems, but abundant venom proteins evolve more rapidly. BMC Genom 16:647
    [Google Scholar]
  157. 157. 
    Gibbs HL, Rossiter W. 2008. Rapid evolution by positive selection and gene gain and loss: PLA2 venom genes in closely related Sistrurus rattlesnakes with divergent diets. J. Mol. Evol. 66:2151–66
    [Google Scholar]
  158. 158. 
    Margres MJ, Walls R, Suntravat M, Lucena S, Sanchez EE, Rokyta DR 2016. Functional characterizations of venom phenotypes in the eastern diamondback rattlesnake (Crotalus adamanteus) and evidence for expression-driven divergence in toxic activities among populations. Toxicon 119:28–38
    [Google Scholar]
  159. 159. 
    Pegueroles C, Laurie S, Alba MM 2013. Accelerated evolution after gene duplication: a time-dependent process affecting just one copy. Mol. Biol. Evol. 30:1830–42
    [Google Scholar]
  160. 160. 
    Nakashima K, Ogawa T, Oda N, Hattori M, Sakaki Y, Kihara H et al. 1993. Accelerated evolution of Trimeresurus flavoviridis venom gland phospholipase A2 isozymes. PNAS 90:135964–68
    [Google Scholar]
  161. 161. 
    Ogawa T, Kitajima M, Nakashima K, Sakaki Y, Ohno M 1995. Molecular evolution of group II phospholipases A2. J. Mol. Evol. 41:867–77
    [Google Scholar]
  162. 162. 
    Fujimi TJ, Nakajyo T, Nishimura E, Ogura E, Tsuchiya T, Tamiya T 2003. Molecular evolution and diversification of snake toxin genes, revealed by analysis of intron sequences. Gene 313:111–18
    [Google Scholar]
  163. 163. 
    Doley R, Mackessy SP, Kini RM 2009. Role of accelerated segment switch in exons to alter targeting (ASSET) in the molecular evolution of snake venom proteins. BMC Evol. Biol. 9:146
    [Google Scholar]
  164. 164. 
    Doley R, Pahari S, Mackessy SP, Kini RM 2008. Accelerated exchange of exon segments in Viperid three-finger toxin genes (Sistrurus catenatus edwardsii; Desert Massasauga). BMC Evol. Biol. 8:196
    [Google Scholar]
  165. 165. 
    Kini RM, Chinnasamy A. 2010. Nucleotide sequence determines the accelerated rate of point mutations. Toxicon 56:295–304
    [Google Scholar]
  166. 166. 
    Pawlak J, Kini RM. 2008. Unique gene organization of colubrid three-finger toxins: complete cDNA and gene sequences of denmotoxin, a bird-specific toxin from colubrid snake Boiga dendrophila (Mangrove Catsnake). Biochimie 90:868–77
    [Google Scholar]
  167. 167. 
    Moura-da-Silva AM, Furlan MS, Caporrino MC, Grego KF, Portes-Junior JA et al. 2011. Diversity of metalloproteinases in Bothrops neuwiedi snake venom transcripts: evidences for recombination between different classes of SVMPs. BMC Genet 12:94
    [Google Scholar]
  168. 168. 
    Sunagar K, Jackson T, Undheim E, Ali S, Antunes A, Fry BG 2013. Three-fingered RAVERs: Rapid Accumulation of Variations in Exposed Residues of snake venom toxins. Toxins 5:2172–208
    [Google Scholar]
  169. 169. 
    Kini RM. 2018. Accelerated evolution of toxin genes: exonization and intronization in snake venom disintegrin/metalloprotease genes. Toxicon 148:16–25
    [Google Scholar]
  170. 170. 
    Dowell NL, Giorgianni MW, Kassner VA, Selegue JE, Sanchez EE, Carroll SB 2016. The deep origin and recent loss of venom toxin genes in rattlesnakes. Curr. Biol. 26:2434–45
    [Google Scholar]
  171. 171. 
    Hargreaves AD, Swain MT, Logan DW, Mulley JF 2014. Testing the Toxicofera: Comparative transcriptomics casts doubt on the single, early evolution of the reptile venom system. Toxicon 92:140–56
    [Google Scholar]
  172. 172. 
    Koh CY, Kini RM. 2012. From snake venom toxins to therapeutics—cardiovascular examples. Toxicon 59:497–506
    [Google Scholar]
  173. 173. 
    Koh CY, Modahl CM, Kulkarni N, Kini RM 2018. Toxins are an excellent source of therapeutic agents against cardiovascular diseases. Semin. Thromb. Hemost. 44:691–706
    [Google Scholar]
  174. 174. 
    Pennington MW, Czerwinski A, Norton RS 2018. Peptide therapeutics from venom: current status and potential. Bioorg. Med. Chem. 26:2738–58
    [Google Scholar]
  175. 175. 
    Harvey AL. 2014. Toxins and drug discovery. Toxicon 92:193–200
    [Google Scholar]
  176. 176. 
    Gainer JV, Morrow JD, Loveland A, King DJ, Brown NJ 1998. Effect of bradykinin-receptor blockade on the response to angiotensin-converting-enzyme inhibitor in normotensive and hypertensive subjects. N. Engl. J. Med. 339:1285–92
    [Google Scholar]
  177. 177. 
    Smith CG, Vane JR. 2003. The discovery of captopril. FASEB J 17:788–89
    [Google Scholar]
  178. 178. 
    Ferreira SH. 2010. From the Bothrops Jararaca bradykinin potentiating peptides to angiotensin converting enzyme inhibitors. Toxins and Hemostasis: From Bench to Bedside RM Kini, KJ Clemetson, FS Markland, MA McLane, T Morita 13–17 Dordrecht: Springer Neth.
    [Google Scholar]
  179. 179. 
    Schweitz H, Vigne P, Moinier D, Frelin C, Lazdunski M 1992. A new member of the natriuretic peptide family is present in the venom of the green mamba (Dendroaspis angusticeps). J. Biol. Chem. 267:13928–32
    [Google Scholar]
  180. 180. 
    Chen HH, Lainchbury JG, Burnett JC Jr 2002. Natriuretic peptide receptors and neutral endopeptidase in mediating the renal actions of a new therapeutic synthetic natriuretic peptide Dendroaspis natriuretic peptide. J. Am. Coll. Cardiol. 40:1186–91
    [Google Scholar]
  181. 181. 
    Lisy O, Huntley BK, McCormick DJ, Kurlansky PA, Burnett JC Jr 2008. Design, synthesis, and actions of a novel chimeric natriuretic peptide: CD-NP. J. Am. Coll. Cardiol. 52:60–68
    [Google Scholar]
  182. 182. 
    Ichiki T, Dzhoyashvili N, Burnett JC Jr 2019. Natriuretic peptide based therapeutics for heart failure: Cenderitide: a novel first-in-class designer natriuretic peptide. Int. J. Cardiol. 281:166–71
    [Google Scholar]
  183. 183. 
    Kawakami R, Lee CYW, Scott C, Bailey KR, Schirger JA et al. 2018. A human study to evaluate safety, tolerability, and cyclic GMP activating properties of cenderitide in subjects with stable chronic heart failure. Clin. Pharmacol. Ther. 104:546–52
    [Google Scholar]
  184. 184. 
    Sridharan S, Kini RM. 2018. Decoding the molecular switches of natriuretic peptides which differentiate its vascular and renal functions. Biochem. J. 475:399–413
    [Google Scholar]
  185. 185. 
    Sridharan S, Kini RM. 2015. Tail wags the dog: Activity of krait natriuretic peptide is determined by its C-terminal tail in a natriuretic peptide receptor-independent manner. Biochem. J. 469:255–66
    [Google Scholar]
  186. 186. 
    Knight LC, Baidoo KE, Romano JE, Gabriel JL, Maurer AH 2000. Imaging pulmonary emboli and deep venous thrombi with 99mTc-bitistatin, a platelet-binding polypeptide from viper venom. J. Nucl. Med. 41:1056–64
    [Google Scholar]
  187. 187. 
    Knight LC, Romano JE, Bright LT, Agelan A, Kantor S, Maurer AH 2007. Platelet binding and biodistribution of [99mTc]rBitistatin in animal species and humans. Nucl. Med. Biol. 34:855–63
    [Google Scholar]
  188. 188. 
    Temple Univ 2015. Phase II investigation of 99mTc-rBitistatin for imaging venous thrombosis ClinicalTrials.gov, ID NCT00808626. https://clinicaltrials.gov/ct2/show/NCT00808626
  189. 189. 
    Matsui T, Hamako J, Titani K 2010. Structure and function of snake venom proteins affecting platelet plug formation. Toxins 2:10–23
    [Google Scholar]
  190. 190. 
    Perchuc AM, Wilmer M. 2010. Diagnostic use of snake venom components in the coagulation laboratory. Toxins and Hemostasis: From Bench to Bedside RM Kini, KJ Clemetson, FS Markland, MA McLane, T Morita 747–66 Dordrecht: Springer Neth.
    [Google Scholar]
  191. 191. 
    Brinkhous KM, Read MS, Reddick RL, Griggs TR 1981. Pathophysiology of platelet-aggregating von Willebrand factor: applications of the venom coagglutinin vWF assay. Ann. N.Y. Acad. Sci. 370:191–204
    [Google Scholar]
  192. 192. 
    Fukuda K, Doggett T, Laurenzi IJ, Liddington RC, Diacovo TG 2005. The snake venom protein botrocetin acts as a biological brace to promote dysfunctional platelet aggregation. Nat. Struct. Mol. Biol. 12:152–59
    [Google Scholar]
  193. 193. 
    Kini RM. 2006. Anticoagulant proteins from snake venoms: structure, function and mechanism. Biochem. J. 397:377–87
    [Google Scholar]
  194. 194. 
    Castro HC, Zingali RB, Albuquerque MG, Pujol-Luz M, Rodrigues CR 2004. Snake venom thrombin-like enzymes: from reptilase to now. Cell. Mol. Life Sci. 61:843–56
    [Google Scholar]
  195. 195. 
    Sherman DG, Atkinson RP, Chippendale T, Levin KA, Ng K et al. 2000. Intravenous ancrod for treatment of acute ischemic stroke: the STAT study: a randomized controlled trial. Stroke Treatment with Ancrod Trial. JAMA 283:2395–403
    [Google Scholar]
  196. 196. 
    Levy DE, del Zoppo GJ, Demaerschalk BM, Demchuk AM, Diener HC et al. 2009. Ancrod in acute ischemic stroke: results of 500 subjects beginning treatment within 6 hours of stroke onset in the ancrod stroke program. Stroke 40:3796–803
    [Google Scholar]
  197. 197. 
    Nordmark Arzneimittel GmbH & Co. KG 2018. Efficacy, safety, and tolerability of ancrod in patients with sudden hearing loss ClinicalTrials.gov, ID NCT01621256. https://clinicaltrials.gov/ct2/show/NCT01621256
  198. 198. 
    Lei Z, Shi Hong L, Li L, Tao YG, Yong Ling W et al. 2011. Batroxobin mobilizes circulating endothelial progenitor cells in patients with deep vein thrombosis. Clin. Appl. Thromb. Hemost. 17:75–79
    [Google Scholar]
  199. 199. 
    Xu G, Liu X, Zhu W, Yin Q, Zhang R, Fan X 2007. Feasibility of treating hyperfibrinogenemia with intermittently administered batroxobin in patients with ischemic stroke/transient ischemic attack for secondary prevention. Blood Coagul. Fibrinolysis 18:193–97
    [Google Scholar]
  200. 200. 
    Hu HM, Chen L, Frary CE, Chang CC, Hui H et al. 2015. The beneficial effect of Batroxobin on blood loss reduction in spinal fusion surgery: a prospective, randomized, double-blind, placebo-controlled study. Arch. Orthop. Trauma Surg. 135:491–97
    [Google Scholar]
  201. 201. 
    Zeng Z, Xiao P, Chen J, Wei Y 2009. Are batroxobin agents effective for perioperative hemorrhage in thoracic surgery? A systematic review of randomized controlled trials. Blood Coagul. Fibrinolysis 20:101–7
    [Google Scholar]
  202. 202. 
    Yamada D, Morita T. 1999. CA-1 method, a novel assay for quantification of normal prothrombin using a Ca2+-dependent prothrombin activator, carinactivase-1. Thromb. Res. 94:221–26
    [Google Scholar]
  203. 203. 
    Kini RM, Koh CY. 2016. Metalloproteases affecting blood coagulation, fibrinolysis and platelet aggregation from snake venoms: definition and nomenclature of interaction sites. Toxins 8:10284
    [Google Scholar]
  204. 204. 
    Takacs Z, Wilhelmsen KC, Sorota S 2001. Snake α-neurotoxin binding site on the Egyptian cobra (Naja haje) nicotinic acetylcholine receptor is conserved. Mol. Biol. Evol. 18:1800–9
    [Google Scholar]
  205. 205. 
    Takacs Z, Wilhelmsen KC, Sorota S 2004. Cobra (Naja spp.) nicotinic acetylcholine receptor exhibits resistance to Erabu sea snake (Laticauda semifasciata) short-chain α-neurotoxin. J. Mol. Evol. 58:516–26
    [Google Scholar]
  206. 206. 
    Perales J, Neves-Ferreira AG, Valente RH, Domont GB 2005. Natural inhibitors of snake venom hemorrhagic metalloproteinases. Toxicon 45:1013–20
    [Google Scholar]
  207. 207. 
    Dunn RD, Broady KW. 2001. Snake inhibitors of phospholipase A2 enzymes. Biochim. Biophys. Acta 1533:29–37
    [Google Scholar]
  208. 208. 
    Campos PC, de Melo LA, Dias GLF, Fortes-Dias CL 2016. Endogenous phospholipase A2 inhibitors in snakes: a brief overview. J. Venom. Anim. Toxins Incl. Trop. Dis. 22:37–37
    [Google Scholar]
  209. 209. 
    Bastos VA, Gomes-Neto F, Perales J, Neves-Ferreira AGC, Valente RH 2016. Natural inhibitors of snake venom metalloendopeptidases: history and current challenges. Toxins 8:250
    [Google Scholar]
  210. 210. 
    Aoki N, Sakiyama A, Deshimaru M, Terada S 2007. Identification of novel serum proteins in a Japanese viper: homologs of mammalian PSP94. Biochem. Biophys. Res. Commun. 359:330–34
    [Google Scholar]
  211. 211. 
    Shioi N, Ogawa E, Mizukami Y, Abe S, Hayashi R, Terada S 2013. Small serum protein-1 changes the susceptibility of an apoptosis-inducing metalloproteinase HV1 to a metalloproteinase inhibitor in habu snake (Trimeresurus flavoviridis). J. Biochem. 153:121–29
    [Google Scholar]
  212. 212. 
    Shioi N, Deshimaru M, Terada S 2014. Structural analysis and characterization of new small serum proteins from the serum of a venomous snake (Gloydius blomhoffii). Biosci. Biotechnol. Biochem. 78:410–19
    [Google Scholar]
  213. 213. 
    Shioi N, Nishijima A, Terada S 2015. Flavorase, a novel non-haemorrhagic metalloproteinase in Protobothrops flavoviridis venom, is a target molecule of small serum protein-3. J. Biochem. 158:37–48
    [Google Scholar]
  214. 214. 
    Lizano S, Lomonte B, Fox JW, Gutiérrez JM 1997. Biochemical characterization and pharmacological properties of a phospholipase A2 myotoxin inhibitor from the plasma of the snake Bothrops asper. Biochem. J 326:3853–59
    [Google Scholar]
  215. 215. 
    Lizano S, Angulo Y, Lomonte B, Fox JW, Lambeau G et al. 2000. Two phospholipase A2 inhibitors from the plasma of Cerrophidion (Bothrops) godmani which selectively inhibit two different group-II phospholipase A2 myotoxins from its own venom: isolation, molecular cloning and biological properties. Biochem. J. 346:3631–39
    [Google Scholar]
  216. 216. 
    Nobuhisa I, Inamasu S, Nakai M, Tatsui A, Mimori T et al. 1997. Characterization and evolution of a gene encoding a Trimeresurus flavoviridis serum protein that inhibits basic phospholipase A2 isozymes in the snake's venom. Eur. J. Biochem. 249:838–45
    [Google Scholar]
  217. 217. 
    Perales J, Villela C, Domont GB, Choumet V, Saliou B et al. 1995. Molecular structure and mechanism of action of the crotoxin inhibitor from Crotalus durissus terrificus serum. Eur. J. Biochem. 227:19–26
    [Google Scholar]
  218. 218. 
    Aoki N, Matsuo H, Deshimaru M, Terada S 2008. Accelerated evolution of small serum proteins (SSPs)—the PSP94 family proteins in a Japanese viper. Gene 426:7–14
    [Google Scholar]
  219. 219. 
    Tanaka Y, Oyama S, Hori S, Ushio K, Shioi N et al. 2013. Accelerated evolution of fetuin family proteins in Protobothrops flavoviridis (habu snake) serum and the discovery of an L1-like genomic element in the intronic sequence of a fetuin-encoding gene. Biosci. Biotechnol. Biochem. 77:582–90
    [Google Scholar]
/content/journals/10.1146/annurev-animal-021419-083626
Loading
/content/journals/10.1146/annurev-animal-021419-083626
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error