1932

Abstract

Snakebite envenoming kills and maims hundreds of thousands of people every year, especially in the rural settings of tropical regions. Envenomings are still treated with animal-derived antivenoms, which have prevented many lives from being lost but which are also medicines in need of innovation. Strides are being made to improve envenoming therapies, with promising efforts made toward optimizing manufacturing and quality aspects of existing antivenoms, accelerating research and development of recombinant antivenoms based on monoclonal antibodies, and repurposing of small-molecule inhibitors that block key toxins. Here, we review the most recent advances in these fields and discuss therapeutic opportunities and limitations for different snakebite treatment modalities. Finally, we discuss challenges related to preclinical and clinical evaluation, regulatory pathways, large-scale manufacture, and distribution and access that need to be addressed to fulfill the goals of the World Health Organization's global strategy to prevent and control snakebite envenoming.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pharmtox-022024-033544
2025-01-23
2025-02-15
Loading full text...

Full text loading...

/deliver/fulltext/pharmtox/65/1/annurev-pharmtox-022024-033544.html?itemId=/content/journals/10.1146/annurev-pharmtox-022024-033544&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. Primers 3::17063
    [Crossref] [Google Scholar]
  2. 2.
    Kasturiratne A, Wickremasinghe AR, de Silva N, Gunawardena NK, Pathmeswaran A, et al. 2008.. The global burden of snakebite: a literature analysis and modelling based on regional estimates of envenoming and deaths. . PLOS Med. 5:(11):e218
    [Crossref] [Google Scholar]
  3. 3.
    Harrison RA, Hargreaves A, Wagstaff SC, Faragher B, Lalloo DG. 2009.. Snake envenoming: a disease of poverty. . PLOS Negl. Trop. Dis. 3:(12):e569
    [Crossref] [Google Scholar]
  4. 4.
    Gutiérrez JM. 2021.. Snakebite envenomation as a neglected tropical disease: new impetus for confronting an old scourge. . In Handbook of Venoms and Toxins of Reptiles, ed. SP Mackessy , pp. 47183. Boca Raton, FL:: CRC Press. , 2nd ed..
    [Google Scholar]
  5. 5.
    WHO (World Health Organ.). 2019.. Snakebite Envenoming: A Strategy for Prevention and Control. Geneva:: WHO. https://www.who.int/publications/i/item/9789241515641
    [Google Scholar]
  6. 6.
    Squaiella-Baptistão CC, Sant'Anna OA, Marcelino JR, Tambourgi DV. 2018.. The history of antivenoms development: beyond Calmette and Vital Brazil. . Toxicon 150::8695
    [Crossref] [Google Scholar]
  7. 7.
    WHO (World Health Organ.). 2017.. WHO Guidelines for the Production, Control and Regulation of Snake Antivenom Immunoglobulins. Geneva:: WHO. https://www.who.int/publications/m/item/snake-antivenom-immunoglobulins-annex-5-trs-no-1004
    [Google Scholar]
  8. 8.
    WHO (World Health Organ.). 2023.. Target Product Profiles for Animal Plasma-Derived Antivenoms: Antivenoms for Treatment of Snakebite Envenoming in Sub-Saharan Africa. Geneva:: WHO. https://www.who.int/publications/i/item/9789240074569
    [Google Scholar]
  9. 9.
    Gutiérrez JM, Albulescu L-O, Clare RH, Casewell NR, Abd El-Aziz TM, et al. 2021.. The search for natural and synthetic inhibitors that would complement antivenoms as therapeutics for snakebite envenoming. . Toxins 13:(7):451
    [Crossref] [Google Scholar]
  10. 10.
    Mackessy SP, ed. 2021.. Handbook of Venoms and Toxins of Reptiles. Boca Raton, FL:: CRC Press. 680 pp. , 2nd ed..
    [Google Scholar]
  11. 11.
    Borri J, Gutiérrez JM, Knudsen C, Habib AG, Goldstein M, Tuttle A. 2024.. Landscape of toxin-neutralizing therapeutics for snakebite envenoming (2015–2022): setting the stage for an R&D agenda. . PLOS Negl. Trop. Dis. 18:(3):e0012052
    [Crossref] [Google Scholar]
  12. 12.
    Gutiérrez JM. 2012.. Improving antivenom availability and accessibility: science, technology, and beyond. . Toxicon 60:(4):67687
    [Crossref] [Google Scholar]
  13. 13.
    León G, Vargas M, Segura Á, Herrera M, Villalta M, et al. 2018.. Current technology for the industrial manufacture of snake antivenoms. . Toxicon 151::6373
    [Crossref] [Google Scholar]
  14. 14.
    Casewell NR, Jackson TNW, Laustsen AH, Sunagar K. 2020.. Causes and consequences of snake venom variation. . Trends Pharmacol. Sci. 41:(8):57081
    [Crossref] [Google Scholar]
  15. 15.
    Calvete JJ. 2017.. Venomics: integrative venom proteomics and beyond. . Biochem. J. 474:(5):61134
    [Crossref] [Google Scholar]
  16. 16.
    Tasoulis T, Pukala TL, Isbister GK. 2022.. Investigating toxin diversity and abundance in snake venom proteomes. . Front. Pharmacol. 12::768015
    [Crossref] [Google Scholar]
  17. 17.
    Gómez A, Sánchez A, Durán G, Cordero D, Segura Á, et al. 2022.. Intrageneric cross-reactivity of monospecific rabbit antisera against venoms of the medically most important Bitis spp. and Echis spp. African snakes. . PLOS Negl. Trop. Dis. 16:(8):e0010643
    [Crossref] [Google Scholar]
  18. 18.
    Calvete JJ, Rodríguez Y, Quesada-Bernat S, Pla D. 2018.. Toxin-resolved antivenomics-guided assessment of the immunorecognition landscape of antivenoms. . Toxicon 148::10722
    [Crossref] [Google Scholar]
  19. 19.
    Guerrero-Garzón JF, Bénard-Valle M, Restano-Cassulini R, Zamudio F, Corzo G, et al. 2018.. Cloning and sequencing of three-finger toxins from the venom glands of four Micrurus species from Mexico and heterologous expression of an alpha-neurotoxin from Micrurus diastema. . Biochimie 147::11421
    [Crossref] [Google Scholar]
  20. 20.
    de la Rosa G, Olvera F, Archundia IG, Lomonte B, Alagón A, Corzo G. 2019.. Horse immunization with short-chain consensus α-neurotoxin generates antibodies against broad spectrum of elapid venomous species. . Nat. Commun. 10:(1):3642
    [Crossref] [Google Scholar]
  21. 21.
    Rivera-de-Torre E, Rimbault C, Jenkins TP, Sørensen CV, Damsbo A, et al. 2022.. Strategies for heterologous expression, synthesis, and purification of animal venom toxins. . Front. Bioeng. Biotechnol. 9::811905
    [Crossref] [Google Scholar]
  22. 22.
    Puschhof J, Post Y, Beumer J, Kerkkamp HM, Bittenbinder M, et al. 2021.. Derivation of snake venom gland organoids for in vitro venom production. . Nat. Protoc. 16:(3):1494510
    [Crossref] [Google Scholar]
  23. 23.
    Bermúdez-Méndez E, Fuglsang-Madsen A, Føns S, Lomonte B, Gutiérrez JM, Laustsen AH. 2018.. Innovative immunization strategies for antivenom development. . Toxins 10:(11):452
    [Crossref] [Google Scholar]
  24. 24.
    Fox CB, Khandhar AP, Khuu L, Phan T, Kinsey R, et al. 2023.. Physicochemical and immunological effects of adjuvant formulations with snake venom antigens for immunization of horses for antivenom production. . Toxicon 232::107229
    [Crossref] [Google Scholar]
  25. 25.
    Chotwiwatthanakun C, Pratanaphon R, Akesowan S, Sriprapat S, Ratanabanangkoon K. 2001.. Production of potent polyvalent antivenom against three elapid venoms using a low dose, low volume, multi-site immunization protocol. . Toxicon 39:(10):148794
    [Crossref] [Google Scholar]
  26. 26.
    Menzies SK, Dawson CA, Crittenden E, Edge RJ, Hall SR, et al. 2022.. Virus-like particles displaying conserved toxin epitopes stimulate polyspecific, murine antibody responses capable of snake venom recognition. . Sci. Rep. 12:(1):11328
    [Crossref] [Google Scholar]
  27. 27.
    Wagstaff SC, Laing GD, Theakston RDG, Papaspyridis C, Harrison RA. 2006.. Bioinformatics and multiepitope DNA immunization to design rational snake antivenom. . PLOS Med. 5:(10):e209
    [Crossref] [Google Scholar]
  28. 28.
    Ramos HR, Junqueira-de-Azevedo I de LM, Novo JB, Castro K, Duarte CG, et al. 2016.. A heterologous multiepitope DNA prime/recombinant protein boost immunisation strategy for the development of an antiserum against Micrurus corallinus (coral snake) venom. . PLOS Negl. Trop. Dis. 10:(3):e0004484
    [Crossref] [Google Scholar]
  29. 29.
    Arroyo C, Solano S, Segura Á, Herrera M, Estrada R, et al. 2017.. Cross-reactivity and cross-immunomodulation between venoms of the snakes Bothrops asper, Crotalus simus and Lachesis stenophrys, and its effect in the production of polyspecific antivenom for Central America. . Toxicon 138::4348
    [Crossref] [Google Scholar]
  30. 30.
    Laustsen AH, Engmark M, Clouser C, Timberlake S, Vigneault F, et al. 2017.. Exploration of immunoglobulin transcriptomes from mice immunized with three-finger toxins and phospholipases A2 from the Central American coral snake, Micrurus nigrocinctus. . PeerJ 5::e2924
    [Crossref] [Google Scholar]
  31. 31.
    Ratanabanangkoon K, Tan KY, Eursakun S, Tan CH, Simsiriwong P, et al. 2016.. A simple and novel strategy for the production of a pan-specific antiserum against elapid snakes of Asia. . PLOS Negl. Trop. Dis. 10:(4):e0004565
    [Crossref] [Google Scholar]
  32. 32.
    Lomonte B, Calvete JJ. 2017.. Strategies in ‘snake venomics’ aiming at an integrative view of compositional, functional, and immunological characteristics of venoms. . J. Venom. Anim. Toxins Trop. Dis. 23::26
    [Crossref] [Google Scholar]
  33. 33.
    Laustsen AH, Lohse B, Lomonte B, Engmark M, Gutiérrez JM. 2015.. Selecting key toxins for focused development of elapid snake antivenoms and inhibitors guided by a toxicity score. . Toxicon 104::4345
    [Crossref] [Google Scholar]
  34. 34.
    Vargas M, Segura Á, Villalta M, Herrera M, Gutiérrez JM, León G. 2015.. Purification of equine whole IgG snake antivenom by using an aqueous two phase system as a primary purification step. . Biologicals 43:(1):3746
    [Crossref] [Google Scholar]
  35. 35.
    Burnouf T, Griffiths E, Padilla A, Seddik S, Stephano MA, Gutiérrez J-M. 2004.. Assessment of the viral safety of antivenoms fractionated from equine plasma. . Biologicals 32:(3):11528
    [Crossref] [Google Scholar]
  36. 36.
    Segura Á, Herrera M, Villalta M, Vargas M, Gutiérrez JM, León G. 2013.. Assessment of snake antivenom purity by comparing physicochemical and immunochemical methods. . Biologicals 41:(2):9397
    [Crossref] [Google Scholar]
  37. 37.
    Dart RC, Seifert SA, Carroll L, Clark RF, Hall E, et al. 1997.. Affinity-purified, mixed monospecific crotalid antivenom ovine Fab for the treatment of crotalid venom poisoning. . Ann. Emerg. Med. 30:(1):3339
    [Crossref] [Google Scholar]
  38. 38.
    Burnouf T. 2018.. What can be learned in the snake antivenom field from the developments in human plasma derived products?. Toxicon 146::7786
    [Crossref] [Google Scholar]
  39. 39.
    O'Leary MA, Kornhauser RS, Hodgson WC, Isbister GK. 2009.. An examination of the activity of expired and mistreated commercial Australian antivenoms. . Trans. R. Soc. Trop. Med. Hyg. 103:(9):93742
    [Crossref] [Google Scholar]
  40. 40.
    Solano G, Cunningham S, Edge RJ, Duran G, Sanchez A, et al. 2024.. African polyvalent antivenom can maintain pharmacological stability and ability to neutralise murine venom lethality for decades post-expiry: evidence for increasing antivenom shelf life to aid in alleviating chronic shortages. . BMJ Glob. Health 9:(3):e014813
    [Crossref] [Google Scholar]
  41. 41.
    Herrera M, Tattini V Jr., Pitombo RNM, Gutiérrez JM, Borgognoni C, et al. 2014.. Freeze-dried snake antivenoms formulated with sorbitol, sucrose or mannitol: comparison of their stability in an accelerated test. . Toxicon 90::5663
    [Crossref] [Google Scholar]
  42. 42.
    Gutiérrez JM, Solano G, Pla D, Herrera M, Segura Á, et al. 2017.. Preclinical evaluation of the efficacy of antivenoms for snakebite envenoming: state-of-the-art and challenges ahead. . Toxins 9:(5):163
    [Crossref] [Google Scholar]
  43. 43.
    Gutiérrez JM. 2018.. Preclinical assessment of the neutralizing efficacy of snake antivenoms in Latin America and the Caribbean: a review. . Toxicon 146::13850
    [Crossref] [Google Scholar]
  44. 44.
    Soopairin S, Patikorn C, Taychakhoonavudh S. 2023.. Antivenom preclinical efficacy testing against Asian snakes and their availability in Asia: a systematic review. . PLOS ONE 18:(7):e0288723
    [Crossref] [Google Scholar]
  45. 45.
    Bourke LA, Zdenek CN, Neri-Castro E, Bénard-Valle M, Alagón A, et al. 2021.. Pan-American lancehead pit-vipers: coagulotoxic venom effects and antivenom neutralisation of Bothrops asper and B. atrox geographical variants. . Toxins 13:(2):78
    [Crossref] [Google Scholar]
  46. 46.
    Mora-Obando D, Pla D, Lomonte B, Guerrero-Vargas JA, Ayerbe S, Calvete JJ. 2021.. Antivenomics and in vivo preclinical efficacy of six Latin American antivenoms towards south-western Colombian Bothrops asper lineage venoms. . PLOS Negl. Trop. Dis. 15:(2):e0009073
    [Crossref] [Google Scholar]
  47. 47.
    Patel RN, Clare RH, Ledsgaard L, Nys M, Kool J, et al. 2023.. An in vitro assay to investigate venom neurotoxin activity on muscle-type nicotinic acetylcholine receptor activation and for the discovery of toxin-inhibitory molecules. . Biochem. Pharmacol. 216::115758
    [Crossref] [Google Scholar]
  48. 48.
    Ledsgaard L, Laustsen AH, Pus U, Wade J, Villar P, et al. 2022.. In vitro discovery of a human monoclonal antibody that neutralizes lethality of cobra snake venom. . mAbs 14:(1):2085536
    [Crossref] [Google Scholar]
  49. 49.
    Gutiérrez JM, Vargas M, Segura Á, Herrera M, Villalta M, et al. 2021.. In vitro tests for assessing the neutralizing ability of snake antivenoms: toward the 3Rs principles. . Front. Immunol. 11::617429
    [Crossref] [Google Scholar]
  50. 50.
    Sells PG. 2003.. Animal experimentation in snake venom research and in vitro alternatives. . Toxicon 42:(2):11533
    [Crossref] [Google Scholar]
  51. 51.
    Okumu MO, Mbaria JM, Gikunju JK, Mbuthia PG, Madadi VO, et al. 2021.. Artemia salina as an animal model for the preliminary evaluation of snake venom-induced toxicity. . Toxicon X 12::100082
    [Crossref] [Google Scholar]
  52. 52.
    Herrera C, Bolton F, Arias AS, Harrison RA, Gutiérrez JM. 2018.. Analgesic effect of morphine and tramadol in standard toxicity assays in mice injected with venom of the snake Bothrops asper. . Toxicon 154::3541
    [Crossref] [Google Scholar]
  53. 53.
    Durán G, Solano G, Gómez A, Cordero D, Sánchez A, et al. 2021.. Assessing a 6-h endpoint observation time in the lethality neutralization assay used to evaluate the preclinical efficacy of snake antivenoms. . Toxicon X 12::100087
    [Crossref] [Google Scholar]
  54. 54.
    Knudsen C, Casewell NR, Lomonte B, Gutiérrez JM, Vaiyapuri S, Laustsen AH. 2020.. Novel snakebite therapeutics must be tested in appropriate rescue models to robustly assess their preclinical efficacy. . Toxins 12:(9):528
    [Crossref] [Google Scholar]
  55. 55.
    Hamza M, Knudsen C, Gnanathasan CA, Monteiro W, Lewin MR, et al. 2021.. Clinical management of snakebite envenoming: future perspectives. . Toxicon X 11::100079
    [Crossref] [Google Scholar]
  56. 56.
    Williams DJ, Habib AG, Warrell DA. 2018.. Clinical studies of the effectiveness and safety of antivenoms. . Toxicon 150::110
    [Crossref] [Google Scholar]
  57. 57.
    Abouyannis M, Esmail H, Hamaluba M, Ngama M, Mwangudzah H, et al. 2023.. A global core outcome measurement set for snakebite clinical trials. . Lancet Glob. Health 11:(2):e296300
    [Crossref] [Google Scholar]
  58. 58.
    Habib AG, Brown NI. 2018.. The snakebite problem and antivenom crisis from a health-economic perspective. . Toxicon 150::11523
    [Crossref] [Google Scholar]
  59. 59.
    Fan HW, Monteiro WM. 2018.. History and perspectives on how to ensure antivenom accessibility in the most remote areas in Brazil. . Toxicon 151::1523
    [Crossref] [Google Scholar]
  60. 60.
    Potet J, Beran D, Ray N, Alcoba G, Habib AG, et al. 2021.. Access to antivenoms in the developing world: a multidisciplinary analysis. . Toxicon X 12::100086
    [Crossref] [Google Scholar]
  61. 61.
    Patikorn C, Ismail AK, Abidin SAZ, Blanco FB, Blessmann J, et al. 2022.. Situation of snakebite, antivenom market and access to antivenoms in ASEAN countries. . BMJ Glob. Health 7:(3):e007639
    [Crossref] [Google Scholar]
  62. 62.
    Laustsen AH, Engmark M, Milbo C, Johannesen J, Lomonte B, et al. 2016.. From fangs to pharmacology: the future of snakebite envenoming therapy. . Curr. Pharm. Des. 22:(34):527093
    [Crossref] [Google Scholar]
  63. 63.
    Pucca MB, Cerni FA, Janke R, Bermúdez-Méndez E, Ledsgaard L, et al. 2019.. History of envenoming therapy and current perspectives. . Front. Immunol. 10::1598
    [Crossref] [Google Scholar]
  64. 64.
    Miersch S, de la Rosa G, Friis R, Ledsgaard L, Boddum K, et al. 2022.. Synthetic antibodies block receptor binding and current-inhibiting effects of α-cobratoxin from Naja kaouthia. . Protein Sci. 31:(5):e4296
    [Crossref] [Google Scholar]
  65. 65.
    Glanville J, Andrade JC, Bellin M, Kim S, Pletnev S, et al. 2022.. Venom protection by antibody from a snakebite hyperimmune subject. . bioRxiv 2022.09.26.507364. https://doi.org/10.1101/2022.09.26.507364
  66. 66.
    Laustsen AH, Karatt-Vellatt A, Masters EW, Arias AS, Pus U, et al. 2018.. In vivo neutralization of dendrotoxin-mediated neurotoxicity of black mamba venom by oligoclonal human IgG antibodies. . Nat. Commun. 9:(1):3928
    [Crossref] [Google Scholar]
  67. 67.
    Ledsgaard L, Wade J, Jenkins TP, Boddum K, Oganesyan I, et al. 2023.. Discovery and optimization of a broadly-neutralizing human monoclonal antibody against long-chain α-neurotoxins from snakes. . Nat. Commun. 14:(1):682
    [Crossref] [Google Scholar]
  68. 68.
    Bailon Calderon H, Yaniro Coronel VO, Cáceres Rey OA, Colque Alave EG, Leiva Duran WJ, et al. 2020.. Development of nanobodies against hemorrhagic and myotoxic components of Bothrops atrox snake venom. . Front. Immunol. 11::655
    [Crossref] [Google Scholar]
  69. 69.
    Campos LB, Pucca MB, Silva LC, Pessenda G, Filardi BA, et al. 2020.. Identification of cross-reactive human single-chain variable fragments against phospholipases A2 from Lachesis muta and Bothrops spp venoms. . Toxicon 184::11621
    [Crossref] [Google Scholar]
  70. 70.
    Albulescu L-O, Kazandjian T, Slagboom J, Bruyneel B, Ainsworth S, et al. 2019.. A decoy-receptor approach using nicotinic acetylcholine receptor mimics reveals their potential as novel therapeutics against neurotoxic snakebite. . Front. Pharmacol. 10::848
    [Crossref] [Google Scholar]
  71. 71.
    Khalek IS, Senji Laxme RR, Nguyen YTK, Khochare S, Patel RN, et al. 2024.. Synthetic development of a broadly neutralizing antibody against snake venom long-chain α-neurotoxins. . Sci. Transl. Med. 16:(735):eadk1867
    [Crossref] [Google Scholar]
  72. 72.
    Boulain JC, Ménez A, Couderc J, Faure G, Liacopoulos P, Fromageot P. 1982.. Neutralizing monoclonal antibody specific for Naja nigricollis toxin α: preparation, characterization, and localization of the antigenic binding site. . Biochemistry 21:(12):291015
    [Crossref] [Google Scholar]
  73. 73.
    Knudsen C, Laustsen AH. 2018.. Recent advances in next generation snakebite antivenoms. . Trop. Med. Infect. Dis. 3::42
    [Crossref] [Google Scholar]
  74. 74.
    Calvete JJ, Sanz L, Angulo Y, Lomonte B, Gutiérrez JM. 2009.. Venoms, venomics, antivenomics. . FEBS Lett. 583:(11):173643
    [Crossref] [Google Scholar]
  75. 75.
    Laustsen AH. 2018.. Guiding recombinant antivenom development by omics technologies. . New Biotechnol. 45::1927
    [Crossref] [Google Scholar]
  76. 76.
    Laustsen AH, Lomonte B, Lohse B, Fernández J, Gutiérrez JM. 2015.. Unveiling the nature of black mamba (Dendroaspis polylepis) venom through venomics and antivenom immunoprofiling: identification of key toxin targets for antivenom development. . J. Proteom. 119::12642
    [Crossref] [Google Scholar]
  77. 77.
    Nguyen GTT, O'Brien C, Wouters Y, Seneci L, Gallissà-Calzado A, et al. 2022.. High-throughput proteomics and in vitro functional characterization of the 26 medically most important elapids and vipers from sub-Saharan Africa. . GigaScience 11::giac121
    [Crossref] [Google Scholar]
  78. 78.
    Calvete JJ, Lomonte B. 2015.. A bright future for integrative venomics. . Toxicon 107:(Part B):15962
    [Crossref] [Google Scholar]
  79. 79.
    Laustsen AH, Greiff V, Karatt-Vellatt A, Muyldermans S, Jenkins TP. 2021.. Animal immunization, in vitro display technologies, and machine learning for antibody discovery. . Trends Biotechnol. 39:(12):126373
    [Crossref] [Google Scholar]
  80. 80.
    Laustsen AH, Gutiérrez JM, Knudsen C, Johansen KH, Bermúdez-Méndez E, et al. 2018.. Pros and cons of different therapeutic antibody formats for recombinant antivenom development. . Toxicon 146::15175
    [Crossref] [Google Scholar]
  81. 81.
    Fernández-Quintero ML, Ljungars A, Waibl F, Greiff V, Andersen JT, et al. 2023.. Assessing developability early in the discovery process for novel biologics. . mAbs 15:(1):2171248
    [Crossref] [Google Scholar]
  82. 82.
    Roncolato EC, Campos LB, Pessenda G, Costa e Silva L, Furtado GP, Barbosa JE. 2015.. Phage display as a novel promising antivenom therapy: a review. . Toxicon 93::7984
    [Crossref] [Google Scholar]
  83. 83.
    Ledsgaard L, Kilstrup M, Karatt-Vellatt A, McCafferty J, Laustsen AH. 2018.. Basics of antibody phage display technology. . Toxins 10:(6):236
    [Crossref] [Google Scholar]
  84. 84.
    Ledsgaard L, Ljungars A, Rimbault C, Sørensen CV, Tulika T, et al. 2022.. Advances in antibody phage display technology. . Drug Discov. Today 27:(8):215169
    [Crossref] [Google Scholar]
  85. 85.
    Richard G, Meyers AJ, McLean MD, Arbabi-Ghahroudi M, MacKenzie R, Hall JC. 2013.. In vivo neutralization of α-cobratoxin with high-affinity llama single-domain antibodies (VHHs) and a VHH-Fc antibody. . PLOS ONE 8:(7):e69495
    [Crossref] [Google Scholar]
  86. 86.
    Sørensen CV, Ledsgaard L, Wildenauer HHK, Dahl CH, Ebersole TW, et al. 2023.. Cross-reactivity trends when selecting scFv antibodies against snake toxins using a phage display-based cross-panning strategy. . Sci. Rep. 13:(1):10181
    [Crossref] [Google Scholar]
  87. 87.
    Sørensen CV, Almeida JR, Bohn M-F, Rivera-de-Torre E, Schoffelen S, et al. 2023.. Discovery of a human monoclonal antibody that cross-neutralizes venom phospholipase A2s from three different snake genera. . Toxicon 234::107307
    [Crossref] [Google Scholar]
  88. 88.
    Rivera-de-Torre E, Lampadariou S, Møiniche M, Bohn MF, Kazemi SM, Laustsen AH. 2024.. Discovery of broadly-neutralizing antibodies against brown recluse spider and Gadim scorpion sphingomyelinases using consensus toxins as antigens. . Protein Sci. 33:(3):e4901
    [Crossref] [Google Scholar]
  89. 89.
    Sørensen CV, Fernández J, Adams AC, Wildenauer HHK, Schoffelen S, et al. 2024.. Antibody-dependent enhancement of toxicity of myotoxin II from Bothrops asper. . Nat. Commun. 15:(1):173
    [Crossref] [Google Scholar]
  90. 90.
    Ahmadi S, Benard-Valle M, Boddum K, Cardoso FC, King GF, et al. 2023.. From squid giant axon to automated patch-clamp: electrophysiology in venom and antivenom research. . Front. Pharmacol. 14::1249336
    [Crossref] [Google Scholar]
  91. 91.
    Rimbault C, Knudsen PD, Damsbo A, Boddum K, Ali H, et al. 2023.. A single-chain variable fragment selected against a conformational epitope of a recombinantly produced snake toxin using phage display. . New Biotechnol. 76::2332
    [Crossref] [Google Scholar]
  92. 92.
    Sørensen CV, Hofmann N, Rawat P, Sørensen FV, Ljungars A, et al. 2024.. ExpoSeq: simplified analysis of high-throughput sequencing data from antibody discovery campaigns. . Bioinform. Adv. 4:(1):vbae020
    [Crossref] [Google Scholar]
  93. 93.
    Kini RM, Sidhu SS, Laustsen AH. 2018.. Biosynthetic oligoclonal antivenom (BOA) for snakebite and next-generation treatments for snakebite victims. . Toxins 10:(12):534
    [Crossref] [Google Scholar]
  94. 94.
    Laustsen AH, Johansen KH, Engmark M, Andersen MR. 2016.. Snakebites: costing recombinant antivenoms. . Nature 538:(7623):41
    [Crossref] [Google Scholar]
  95. 95.
    Jenkins TP, Laustsen AH. 2020.. Cost of manufacturing for recombinant snakebite antivenoms. . Front. Bioeng. Biotechnol. 8::703
    [Crossref] [Google Scholar]
  96. 96.
    Laustsen AH, Johansen KH, Engmark M, Andersen MR. 2017.. Recombinant snakebite antivenoms: a cost-competitive solution to a neglected tropical disease?. PLOS Negl. Trop. Dis. 11:(2):e0005361
    [Crossref] [Google Scholar]
  97. 97.
    Benard-Valle M, Wouters Y, Ljungars A, Nguyen GTT, Ahmadi S, et al. 2024.. In vivo neutralization of coral snake venoms with an oligoclonal nanobody mixture in a murine challenge model. . Nat. Commun. 15::4310
    [Crossref] [Google Scholar]
  98. 98.
    Wade J, Rimbault C, Ali H, Ledsgaard L, Rivera-de-Torre E, et al. 2022.. Generation of multivalent nanobody-based proteins with improved neutralization of long α-neurotoxins from elapid snakes. . Bioconjug. Chem. 33:(8):1494504
    [Crossref] [Google Scholar]
  99. 99.
    Tulika T, Pedersen RW, Rimbault C, Ahmadi S, Rivera-de-Torre E, et al. 2023.. Phage display assisted discovery of a pH-dependent anti-α-cobratoxin antibody from a natural variable domain library. . Protein Sci. 32:(12):e4821
    [Crossref] [Google Scholar]
  100. 100.
    Klaus T, Deshmukh S. 2021.. pH-responsive antibodies for therapeutic applications. . J. Biomed. Sci. 28:(1):11
    [Crossref] [Google Scholar]
  101. 101.
    Knudsen C, Jürgensen JA, Føns S, Haack AM, Friis RUW, et al. 2021.. Snakebite envenoming diagnosis and diagnostics. . Front. Immunol. 12::661457
    [Crossref] [Google Scholar]
  102. 102.
    Knudsen C, Jürgensen JA, Knudsen PD, Oganesyan I, Harrison JA, et al. 2023.. Prototyping of a lateral flow assay based on monoclonal antibodies for detection of Bothrops venoms. . Anal. Chim. Acta 1272::341306
    [Crossref] [Google Scholar]
  103. 103.
    Knudsen C, Belfakir SB, Degnegaard P, Jürgensen JA, Haack AM, et al. 2024.. Multiplex lateral flow assay development for snake venom detection in biological matrices. . Sci. Rep. 14:(1):2567
    [Crossref] [Google Scholar]
  104. 104.
    Howes J-M, Theakston RDG, Laing GD. 2007.. Neutralization of the haemorrhagic activities of viperine snake venoms and venom metalloproteinases using synthetic peptide inhibitors and chelators. . Toxicon 49:(5):73439
    [Crossref] [Google Scholar]
  105. 105.
    Rucavado A, Escalante T, Franceschi A, Chaves F, León G, et al. 2000.. Inhibition of local hemorrhage and dermonecrosis induced by Bothrops asper snake venom: effectiveness of early in situ administration of the peptidomimetic metalloproteinase inhibitor batimastat and the chelating agent CaNa2EDTA. . Am. J. Trop. Med. Hyg. 63:(5–6):31319
    [Crossref] [Google Scholar]
  106. 106.
    Lewin MR, Carter RW, Matteo IA, Samuel SP, Rao S, et al. 2022.. Varespladib in the treatment of snakebite envenoming: development history and preclinical evidence supporting advancement to clinical trials in patients bitten by venomous snakes. . Toxins 14:(11):783
    [Crossref] [Google Scholar]
  107. 107.
    Clare RH, Hall SR, Patel RN, Casewell NR. 2021.. Small molecule drug discovery for neglected tropical snakebite. . Trends Pharmacol. Sci. 42:(5):34053
    [Crossref] [Google Scholar]
  108. 108.
    Policy Cures Res. 2022.. Snakebite envenoming medicines database. . Policy Cures Research. https://www.policycuresresearch.org/sbe-medicines-database/
    [Google Scholar]
  109. 109.
    Carter RW, Gerardo CJ, Samuel SP, Kumar S, Kotehal SD, et al. 2023.. The BRAVO clinical study protocol: oral varespladib for inhibition of secretory phospholipase A2 in the treatment of snakebite envenoming. . Toxins 15:(1):22
    [Crossref] [Google Scholar]
  110. 110.
    Abouyannis M, FitzGerald R, Ngama M, Mwangudzah H, Nyambura YK, et al. 2022.. TRUE-1: trial of repurposed unithiol for snakebite envenoming phase 1 (safety, tolerability, pharmacokinetics and pharmacodynamics in healthy Kenyan adults). . Wellcome Open Res. 7::90
    [Crossref] [Google Scholar]
  111. 111.
    Abouyannis M, Nyambura YK, Ngome S, Riako D, Musyoki J, et al. 2024.. Development of an optimised oral regimen of unithiol for the treatment of snakebite envenoming: a phase 1 dose-escalation trial and pharmacokinetic analysis in healthy Kenyan adults. . Lancet. http://dx.doi.org/10.2139/ssrn.4826081
    [Google Scholar]
  112. 112.
    Thumtecho S, Burlet NJ, Ljungars A, Laustsen AH. 2023.. Towards better antivenoms: navigating the road to new types of snakebite envenoming therapies. . J. Venom. Anim. Toxins Trop. Dis. 29::e20230057
    [Crossref] [Google Scholar]
  113. 113.
    Hall SR, Rasmussen SA, Crittenden E, Dawson CA, Bartlett KE, et al. 2023.. Repurposed drugs and their combinations prevent morbidity-inducing dermonecrosis caused by diverse cytotoxic snake venoms. . Nat. Commun. 14:(1):7812
    [Crossref] [Google Scholar]
  114. 114.
    Arias AS, Rucavado A, Gutiérrez JM. 2017.. Peptidomimetic hydroxamate metalloproteinase inhibitors abrogate local and systemic toxicity induced by Echis ocellatus (saw-scaled) snake venom. . Toxicon 132::4049
    [Crossref] [Google Scholar]
  115. 115.
    Bartlett KE, Hall SR, Rasmussen SA, Crittenden E, Dawson CA, et al. 2024.. Dermonecrosis caused by a spitting cobra snakebite results from toxin potentiation and is prevented by the repurposed drug varespladib. . PNAS 121:(19):e2315597121
    [Crossref] [Google Scholar]
  116. 116.
    Rivel M, Solano D, Herrera M, Vargas M, Villalta M, et al. 2016.. Pathogenesis of dermonecrosis induced by venom of the spitting cobra, Naja nigricollis: an experimental study in mice. . Toxicon 119::17179
    [Crossref] [Google Scholar]
  117. 117.
    Mao Y-C, Liu P-Y, Chiang L-C, Lai C-S, Lai K-L, et al. 2018.. Naja atra snakebite in Taiwan. . Clin. Toxicol. 56:(4):27380
    [Crossref] [Google Scholar]
  118. 118.
    Lin C-C, Chaou C-H, Gao S-Y. 2021.. Influential factors of local tissue necrosis after Taiwan cobra bites: a secondary analysis of the clinical significance of venom detection in patients of cobra snakebites. . Toxins 13:(5):338
    [Crossref] [Google Scholar]
  119. 119.
    Albulescu L-O, Hale MS, Ainsworth S, Alsolaiss J, Crittenden E, et al. 2020.. Preclinical validation of a repurposed metal chelator as an early-intervention therapeutic for hemotoxic snakebite. . Sci. Transl. Med. 12:(542):eaay8314
    [Crossref] [Google Scholar]
  120. 120.
    Tiwari N, Aggarwal G, Jain GK, Mittal G. 2022.. Multi-drug loaded microneedles for emergency treatment of snakebite envenomation. . Med. Hypotheses 165::110908
    [Crossref] [Google Scholar]
  121. 121.
    Shabbir A, Shahzad M, Masci P, Gobe GC. 2014.. Protective activity of medicinal plants and their isolated compounds against the toxic effects from the venom of Naja (cobra) species. . J. Ethnopharmacol. 157::22227
    [Crossref] [Google Scholar]
  122. 122.
    Carvalho BMA, Santos JDL, Xavier BM, Almeida JR, Resende LM, et al. 2013.. Snake venom PLA2s inhibitors isolated from Brazilian plants: synthetic and natural molecules. . BioMed Res. Int. 2013::153045
    [Google Scholar]
  123. 123.
    Soares AM, Ticli FK, Marcussi S, Lourenço MV, Januário AH, et al. 2005.. Medicinal plants with inhibitory properties against snake venoms. . Curr. Med. Chem. 12:(22):262541
    [Crossref] [Google Scholar]
  124. 124.
    Rucavado A, Escalante T, Gutiérrez JM. 2004.. Effect of the metalloproteinase inhibitor batimastat in the systemic toxicity induced by Bothrops asper snake venom: understanding the role of metalloproteinases in envenomation. . Toxicon 43:(4):41724
    [Crossref] [Google Scholar]
  125. 125.
    Modahl CM, Saviola AJ, Mackessy SP. 2021.. Integration of transcriptomic and proteomic approaches for snake venom profiling. . Expert Rev. Proteom. 18:(10):82734
    [Crossref] [Google Scholar]
  126. 126.
    Tasoulis T, Isbister GK. 2017.. A review and database of snake venom proteomes. . Toxins 9:(9):290
    [Crossref] [Google Scholar]
  127. 127.
    Chowdhury A, Zdenek CN, Lewin MR, Carter R, Jagar T, et al. 2021.. Venom-induced blood disturbances by Palearctic viperid snakes, and their relative neutralization by antivenoms and enzyme-inhibitors. . Front. Immunol. 12::688802
    [Crossref] [Google Scholar]
  128. 128.
    Albulescu L-O, Xie C, Ainsworth S, Alsolaiss J, Crittenden E, et al. 2020.. A therapeutic combination of two small molecule toxin inhibitors provides broad preclinical efficacy against viper snakebite. . Nat. Commun. 11:(1):6094
    [Crossref] [Google Scholar]
  129. 129.
    Wang Y, Zhang J, Zhang D, Xiao H, Xiong S, Huang C. 2018.. Exploration of the inhibitory potential of varespladib for snakebite envenomation. . Molecules 23:(2):391
    [Crossref] [Google Scholar]
  130. 130.
    Lewin M, Samuel S, Merkel J, Bickler P. 2016.. Varespladib (LY315920) appears to be a potent, broad-spectrum, inhibitor of snake venom phospholipase A2 and a possible pre-referral treatment for envenomation. . Toxins 8:(9):248
    [Crossref] [Google Scholar]
  131. 131.
    Nicholls SJ, Kastelein JJP, Schwartz GG, Bash D, Rosenson RS, et al. 2014.. Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial. . JAMA 311:(3):25262
    [Crossref] [Google Scholar]
  132. 132.
    Waring MJ, Arrowsmith J, Leach AR, Leeson PD, Mandrell S, et al. 2015.. An analysis of the attrition of drug candidates from four major pharmaceutical companies. . Nat. Rev. Drug Discov. 14:(7):47586
    [Crossref] [Google Scholar]
  133. 133.
    Clare RH, Dawson CA, Westhorpe A, Albulescu L-O, Woodley CM, et al. 2024.. Snakebite drug discovery: high-throughput screening to identify novel snake venom metalloproteinase toxin inhibitors. . Front. Pharmacol. 14::1328950
    [Crossref] [Google Scholar]
  134. 134.
    Albulescu L-O, Westhorpe A, Clare RH, Woodley CM, James N, et al. 2024.. Optimizing drug discovery for snakebite envenoming via a high-throughput phospholipase A2 screening platform. . Front. Pharmacol. 14::1331224
    [Crossref] [Google Scholar]
  135. 135.
    Sharafudeen M. 2019.. WIPO Re:Search: Advancing Science for Neglected Tropical Diseases, Malaria and Tuberculosis. Geneva:: WIPO. https://www.wipo.int/edocs/pubdocs/en/wipo_pub_gc_18.pdf
    [Google Scholar]
  136. 136.
    Kalogeropoulos K, Bohn M-F, Jenkins DE, Ledergerber J, Sørensen CV, et al. 2024.. A comparative study of protein structure prediction tools for challenging targets: snake venom toxins. . Toxicon 238::107559
    [Crossref] [Google Scholar]
  137. 137.
    Yingprasertchai S, Bunyasrisawat S, Ratanabanangkoon K. 2003.. Hyaluronidase inhibitors (sodium cromoglycate and sodium auro-thiomalate) reduce the local tissue damage and prolong the survival time of mice injected with Naja kaouthia and Calloselasma rhodostoma venoms. . Toxicon 42:(6):63546
    [Crossref] [Google Scholar]
  138. 138.
    Khedrinia M, Aryapour H, Mianabadi M. 2021.. Prediction of novel inhibitors for Crotalus adamanteusl-amino acid oxidase by repurposing FDA-approved drugs: a virtual screening and molecular dynamics simulation investigation. . Drug Chem. Toxicol. 44:(5):47079
    [Crossref] [Google Scholar]
  139. 139.
    O'Brien J, Lee S-H, Onogi S, Shea KJ. 2016.. Engineering the protein corona of a synthetic polymer nanoparticle for broad-spectrum sequestration and neutralization of venomous biomacromolecules. . J. Am. Chem. Soc. 138:(51):166047
    [Crossref] [Google Scholar]
  140. 140.
    Devi A, Doley R. 2021.. Neutralization of daboxin P activities by rationally designed aptamers. . Toxicon 203::93103
    [Crossref] [Google Scholar]
  141. 141.
    Alomran N, Chinnappan R, Alsolaiss J, Casewell NR, Zourob M. 2022.. Exploring the utility of ssDNA aptamers directed against snake venom toxins as new therapeutics for snakebite envenoming. . Toxins 14:(7):469
    [Crossref] [Google Scholar]
  142. 142.
    Chen Y-J, Tsai C-Y, Hu W-P, Chang L-S. 2016.. DNA aptamers against Taiwan banded krait α-bungarotoxin recognize Taiwan cobra cardiotoxins. . Toxins 8:(3):66
    [Crossref] [Google Scholar]
  143. 143.
    Lewin MR, Samuel SP, Wexler DS, Bickler P, Vaiyapuri S, Mensh BD. 2014.. Early treatment with intranasal neostigmine reduces mortality in a mouse model of Naja naja (Indian cobra) envenomation. . J. Trop. Med. 2014::131835
    [Crossref] [Google Scholar]
  144. 144.
    WHO SEARO (World Health Organ. Reg. Off. SE Asia). 2016.. Guidelines for the Management of Snakebites. New Delhi:: WHO SEARO. https://www.who.int/publications/i/item/9789290225300
    [Google Scholar]
  145. 145.
    D'Este G, Fabris F, Stazi M, Baggio C, Simonato M, et al. 2024.. Agonists of melatonin receptors strongly promote the functional recovery from the neuroparalysis induced by neurotoxic snakes. . PLOS Negl. Trop. Dis. 18:(1):e0011825
    [Crossref] [Google Scholar]
  146. 146.
    Takeda S. 2016.. ADAM and ADAMTS family proteins and snake venom metalloproteinases: a structural overview. . Toxins 8:(5):155
    [Crossref] [Google Scholar]
  147. 147.
    Koludarov I, Jackson TN, Suranse V, Pozzi A, Sunagar K, Mikheyev AS. 2020.. Reconstructing the evolutionary history of a functionally diverse gene family reveals complexity at the genetic origins of novelty. . bioRxiv 583344. https://doi.org/10.1101/583344
  148. 148.
    Bhaumik S, Habib AG, Santra V. 2024.. Strategic priorities for accelerating action to reduce the burden of snakebite. . PLOS Glob. Public Health 4:(2):e0002866
    [Crossref] [Google Scholar]
  149. 149.
    Knudsen C, Ledsgaard L, Dehli RI, Ahmadi S, Sørensen CV, Laustsen AH. 2019.. Engineering and design considerations for next-generation snakebite antivenoms. . Toxicon 167::6775
    [Crossref] [Google Scholar]
  150. 150.
    Laustsen AH. 2024.. Recombinant snake antivenoms get closer to the clinic. . Trends Immunol. 45:(4):22527
    [Crossref] [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-022024-033544
Loading
/content/journals/10.1146/annurev-pharmtox-022024-033544
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