Thematic section: Natural compounds Open access

Anti-inflammatory peptides and proteins from venomous snakes: a short review

Authors

Published
28 April 2025
Section
Thematic section: Natural compounds

Abstract

Inflammation can be acute or chronic. Chronic inflammation is a condition associated with several diseases like cardiovascular and neurodegenerative disorders, and even cancer. The venoms and poisons of several animal species, like bees and snakes, have been used in the Traditional Medicine of many regions for centuries. Although bee venom has been extensively explored and some of its components even experimentally proven to be functional as therapeutics, other animal venoms have been poorly studied in such matter. Despite venomous snakebites are potentially dangerous and fatal to humans, several anti-inflammatory molecules have been found and characterized using experimental models, both in vivo and in vitro. In this review we enlist the polypeptides of venomous snakes that have been isolated and characterized for their anti-inflammatory activity to date. These molecules include the protein Crotoxin isolated from the South American rattlesnake Crotalus durissus terrificus and the few peptides isolated from some Asian elapid snakes. The physiological mechanism of action for each molecule is briefly described. This review highlights the importance of snakes as a source of biological active substances with therapeutic potential.

References

  1. Medzhitov R. Origin and physiological roles of inflammation. Nature. 2008;454:428–35. DOI: https://doi.org/10.1038/nature07201
  2. Okin D, Medzhitov R. Evolution of inflammatory diseases. Curr Biol 2012;22:733–40. DOI: https://doi.org/10.1016/j.cub.2012.07.029
  3. Laveti D, Kumar M, Hemalatha R, et al. Anti-inflammatory treatments for chronic diseases: A review. Inflamm Allergy - Drug Targets 2013;12:349–61. DOI: https://doi.org/10.2174/18715281113129990053
  4. Poorolajal J. The urgency of conducting serological studies for COVID-19. J Res Health Sci 2020;20:1–3. DOI: https://doi.org/10.34172/jrhs.2020.24
  5. Ahmad FB, Anderson RN. The leading causes of death in the US for 2020. JAMA 2021;325:1829–30. DOI: https://doi.org/10.1001/jama.2021.5469
  6. Zhang S, Liu Y, Ye Y, et al. Bee venom therapy: Potential mechanisms and therapeutic applications. Toxicon 2018;148:64–73. DOI: https://doi.org/10.1016/j.toxicon.2018.04.012
  7. Lee G, Bae H. Anti-inflammatory applications of melittin, a major component of bee venom: Detailed mechanism of action and adverse effects. Molecules 2016;21. DOI: https://doi.org/10.3390/molecules21050616
  8. Machkour-M’Rabet S, Hénaut Y, Winterton P, Rojo R. A case of zootherapy with the tarantula Brachypelma vagans Ausserer, 1875 in traditional medicine of the Chol Mayan ethnic group in Mexico. J Ethnobiol Ethnomed 2011;7:1–7. DOI: https://doi.org/10.1186/1746-4269-7-12
  9. Dadar M, Shahali Y, Chakraborty S, et al. Antiinflammatory peptides: current knowledge and promising prospects. Inflamm Res 2019;68:125–45. DOI: https://doi.org/10.1007/s00011-018-1208-x
  10. Franco Vásquez AM, Lazcano Pérez F, Rodríguez-Vargas A, Arreguín Espinosa R. Serpientes venenosas: ¿una problemática o una alternativa en la biotecnología? [Poisonous snakes: a problem or an alternative in biotechnology?] Rev Digit Univ 2024;25:3. DOI: https://doi.org/10.22201/cuaieed.16076079e.2024.25.2.3
  11. Alvarez-Flores MP, Correia Batista I de F, Villas Boas IM, et al. Snake and arthropod venoms: Search for inflammatory activity in human cells involved in joint diseases. Toxicon 2024;238:107568. DOI: https://doi.org/10.1016/j.toxicon.2023.107568
  12. Neri Castro EE, Bénard-Valle M, Alagón A, et al. Serpientes venenosas en México: una revisión al estudio de los venenos, los antivenenos y la epidemiología. [Venomous snakes in Mexico: a review of the study of venoms, antivenoms and epidemiology.] Rev Latinoam Herpetol 2020;3:5. DOI: https://doi.org/10.22201/fc.25942158e.2020.2.205
  13. María Gutiérrez J. Envenenamientos por mordeduras de serpientes en América Latina y el Caribe: Una visión integral de carácter regional TT - Snakebite poisoning in Latin America and the Caribbean: An integral view from a regional perspective. Bol malariol salud Ambient 2011;51:1–16.
  14. Franco-Vásquez AM, Lazcano-Pérez F, Mejía-Sánchez MA, et al. Structural, biochemical and immunochemical characterization of an acidic phospholipase A2 from Lachesis acrochorda (Viperidae: Crotalinae) venom. Toxicon 2024;237:107528. DOI: https://doi.org/10.1016/j.toxicon.2023.107528
  15. Moro PA, Assisi F, Cassetti F, et al. Toxicological hazards of natural environments: Clinical reports from Poison Control Centre of Milan. Urban For Urban Green 2009;8:179–86. DOI: https://doi.org/10.1016/j.ufug.2009.02.007
  16. Paolino G, Di Nicola MR, Avella I, Mercuri SR. Venomous bites, stings and poisoning by european vertebrates as an overlooked and emerging medical problem: recognition, clinical aspects and therapeutic management. Life 2023;13:1228. DOI: https://doi.org/10.3390/life13061228
  17. Lazcano-Pérez F, Franco-Vásquez AM. Serpientes de cascabel , recurso químico invaluable. [Rattlesnakes, an invaluable chemical resource.] Rev Univ UAEMex 2023;44–7.
  18. Lazcano-Pérez F, Rangel-López E, Robles-Bañuelos B, et al. Chemical structure of three basic Asp-49 phospholipases A2 isolated from Crotalus molossus nigrescens venom with cytotoxic activity against cancer cells. Toxicon 2022;210:25–31. DOI: https://doi.org/10.1016/j.toxicon.2022.02.013
  19. Deshwal A, Phan P, Datta J, et al. A meta-analysis of the protein components in rattlesnake venom. Toxins (Basel) 2021;13:372. DOI: https://doi.org/10.3390/toxins13060372
  20. Nunes FP., Zychar BC, Della-Casa MS, et al. Crotoxin is responsible for the long lasting anti-inflammatory effect of C. durissus terrificus snake venom- involvement of formyl peptide receptors. Toxicon 2010;55:1100–6. DOI: https://doi.org/10.1016/j.toxicon.2009.12.011
  21. Nunes FPB, Sampaio SC, Santoro ML, Sousa-e-Silva MCC. Long-lasting anti-inflammatory properties of Crotalus durissus terrificus snake venom in mice. Toxicon 2007;49:1090–8. DOI: https://doi.org/10.1016/j.toxicon.2007.01.017
  22. Gimenes da Silva N, Sampio SC, Gonçalves C. LR. Inhibitory effect of C. durissus terrificus venom on chronic edema induced by injection of bacillus Calmette-Guérin. Toxicon 2013;63:98–103. DOI: https://doi.org/10.1016/j.toxicon.2012.12.003
  23. Mejía-Sánchez MA, Clement H, Corrales-García LL, et al. Crotoxin B: heterologous expression, protein folding, immunogenic properties, and irregular presence in Crotalid venoms. Toxins 2022;14:1–18. DOI: https://doi.org/10.3390/toxins14060382
  24. Faure G, Xu H, Saul FA. Crystal structure of crotoxin reveals key residues involved in the stability and toxicity of this potent heterodimeric β-neurotoxin. J Mol Biol 2011;412:176–91. DOI: https://doi.org/10.1016/j.jmb.2011.07.027
  25. Chen YH, Wang YM, Hseu MJ, Tsai IH. Molecular evolution and structure-function relationships of crotoxin-like and asparagine-6-containing phospholipases A2 in pit viper venoms. Biochem J 2004;381:25–34. DOI: https://doi.org/10.1042/BJ20040125
  26. Salvador GHM, Fernandes CAH, Borges RJ, et al. Structural studies with crotoxin B from Crotalus durissus collilineatus venom suggest a heterodimeric assembly formed by two new isoforms. Biochimie 2024;218:46–56. DOI: https://doi.org/10.1016/j.biochi.2023.08.018
  27. Durban J, Sanz L, Trevisan-Silva D, et al. 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 2017;16:3370–90. DOI: https://doi.org/10.1021/acs.jproteome.7b00414
  28. Pettersen EF, Goddard TD, Huang CC, et al. UCSF ChimeraX: Structure visualization for researchers, educators, and developers. Protein Sci 2021;30:70–82. DOI: https://doi.org/10.1002/pro.3943
  29. Lima TS, Neves CL, Zambelli VO, et al. Crotoxin, a rattlesnake toxin, down-modulates functions of bone marrow neutrophils and impairs the Syk-GTPase pathway. Toxicon 2017;136:44–55. DOI: https://doi.org/10.1016/j.toxicon.2017.07.002
  30. Sartim MA, Menaldo DL, Sampaio SV. Immunotherapeutic potential of Crotoxin: anti-inflammatory and immunosuppressive properties. J Venom Anim Toxins Incl Trop Dis 2018;24:39. DOI: https://doi.org/10.1186/s40409-018-0178-3
  31. De Almeida CS, Andrade-Oliveira V, Câmara NOS, et al. Crotoxin from Crotalus durissus terrificus is able to down-modulate the acute intestinal inflammation in mice. PLoS One 2015;10:e0121427. DOI: https://doi.org/10.1371/journal.pone.0121427
  32. Faiad OJ, Francisco AMSDC, Brigatte P, et al. Crotoxin modulates metabolism and secretory activity of peritoneal macrophages from Walker 256 tumor-bearing rats. Toxicon 2022;217:46–55. DOI: https://doi.org/10.1016/j.toxicon.2022.07.011
  33. Neves CL, Barbosa CMV, Ranéia-Silva PA, et al. Crotoxin modulates macrophage phenotypic reprogramming. Toxins (Basel) 2023;15:616. DOI: https://doi.org/10.3390/toxins15100616
  34. Parveen G, Ali H, Sabur Ul Hassan H. Lethal dose (LD50) of the big four snakes-a mini review. Int J Mol Biol 2018;3:76–7. DOI: https://doi.org/10.15406/ijmboa.2018.03.00055
  35. Pitman CRS. Hood-spreading by the mambas of the african genus Dendroaspis. J East Africa Nat Hist Soc 1965;25:110–5.
  36. Young BA, Kardong K V. The functional morphology of hooding in cobras. J Exp Biol 2010;213:1521–8. DOI: https://doi.org/10.1242/jeb.034447
  37. Zhu Q, Huang J, Wang S zhi, et al. Cobrotoxin extracted from Naja atra venom relieves arthritis symptoms through anti-inflammation and immunosuppression effects in rat arthritis model. J Ethnopharmacol 2016;194:1087–95. DOI: https://doi.org/10.1016/j.jep.2016.11.009
  38. Gomes A, Bhattacharya S, Chakraborty M, et al. Anti-arthritic activity of Indian monocellate cobra (Naja kaouthia) venom on adjuvant induced arthritis. Toxicon 2010;55:670–3. DOI: https://doi.org/10.1016/j.toxicon.2009.10.007
  39. Zhu KZ, Liu YL, Gu JH, Qin Z hong. Antinociceptive and anti-Inflammatory effects of orally administrated denatured Naja naja atra venom on murine rheumatoid arthritis models. Evidence-Based Complement Altern Med 2013;2013:616241. DOI: https://doi.org/10.1155/2013/616241
  40. Chen ZX, Zhang HL, Gu ZL, et al. A long-form α-neurotoxin from cobra venom produces potent opioid-independent analgesia. Acta Pharmacol Sin 2006;27:402–8. DOI: https://doi.org/10.1111/j.1745-7254.2006.00293.x
  41. Shi GN, Liu YL, Lin HM, et al. Involvement of cholinergic system in suppression of formalin-induced inflammatory pain by cobratoxin. Acta Pharmacol Sin 2011;32:1233–8. DOI: https://doi.org/10.1038/aps.2011.65
  42. Ruan Y, Yao L, Zhang B, et al. Anti-inflammatory effects of Neurotoxin-Nna, a peptide separated from the venom of Naja naja atra. BMC Complement Altern Med 2013;13:86. DOI: https://doi.org/10.1186/1472-6882-13-86
  43. Stazi M, Fabris F, Tan KY, et al. An agonist of the CXCR4 receptor is therapeutic for the neuroparalysis induced by Bungarus snakes envenoming. Clin Transl Med 2022;12:2–7. DOI: https://doi.org/10.1002/ctm2.651
  44. Yi H, Yu C, Zhang H, et al. Cathelicidin-BF suppresses intestinal inflammation by inhibiting the nuclear factor-κB signaling pathway. Int Immunopharmacol. 2015;28:6169. DOI: https://doi.org/10.1016/j.intimp.2015.05.034
  45. Zhang H, Xia X, Han F, et al. Cathelicidin-BF, a novel antimicrobial peptide from Bungarus fasciatus, attenuates disease in a dextran sulfate sodium model of colitis. Mol Pharm. 2015;12:1648–61. DOI: https://doi.org/10.1021/acs.molpharmaceut.5b00069
  46. Feng J, Wang L, Xie Y, et al. Effects of antimicrobial peptide cathelicidin-BF on diarrhea controlling, immune responses, intestinal inflammation and intestinal barrier. Int Immunopharmacol 2020;85:1–7. DOI: https://doi.org/10.1016/j.intimp.2020.106658
  47. Zhou H, Zou L, Ren H, et al. Cathelicidin-BF regulates the AMPK-SIRT1-NF-κB pathway to ameliorate murine osteoarthritis. Int Immunopharmacol 2024;134:1–12. DOI: https://doi.org/10.1016/j.intimp.2024.112201
  48. Rezaie-Atagholipour M, Ghezellou P, Hesni MA, et al. Sea snakes (Elapidae, Hydrophiinae) in their westernmost extent: an updated and illustrated checklist and key to the species in the Persian Gulf and Gulf of Oman. Zookeys 2016;2016:129–64. DOI: https://doi.org/10.3897/zookeys.622.9939
  49. Wang B, Wang Q, Wang C, et al. A comparative analysis of the proteomes and biological activities of the venoms from two sea snakes, Hydrophis curtus and Hydrophis cyanocinctus, from Hainan, China. Toxicon 2020;187:35–46. DOI: https://doi.org/10.1016/j.toxicon.2020.08.012
  50. Wei L, Gao S, Wu S, et al. Identification and characterization of the first Cathelicidin from sea snakes with potent antimicrobial and anti-inflammatory activity. J Biol Chem 2015;290:16633–52. DOI: https://doi.org/10.1074/jbc.M115.642645
  51. Wang N, Huang Y, Li A, et al. Hydrostatin-TL1, an anti-inflammatory active peptide from the venom gland of Hydrophis cyanocinctus in the South China Sea. Int J Mol Sci 2016;17. DOI: https://doi.org/10.3390/ijms17111940
  52. Zheng Z, Jiang H, Huang Y, et al. Screening of an anti-inflammatory peptide from Hydrophis cyanocinctus and analysis of its activities and mechanism in DSS-induced acute colitis. Sci Rep 2016;6:25672. DOI: https://doi.org/10.1038/srep25672
  53. Zhang C, Guo S, Wang J, et al. Anti-Inflammatory activity and mechanism of Hydrostatin-SN1 from Hydrophis cyanocinctus in interleukin-10 knockout mice. Front Pharmacol 2020;11:1–9. DOI: https://doi.org/10.3389/fphar.2020.00930
  54. Tasoulis T, Isbister GK. A review and database of snake venom proteomes. Toxins 2017;9:290. DOI: https://doi.org/10.3390/toxins9090290
  55. Kakumanu R, Kemp-Harper BK, Silva A, et al. An in vivo examination of the differences between rapid cardiovascular collapse and prolonged hypotension induced by snake venom. Sci Rep 2019;9:20231. DOI: https://doi.org/10.1038/s41598-019-56643-0
  56. Siigur J, Aaspõllu A, Siigur E. Biochemistry and pharmacology of proteins and peptides purified from the venoms of the snakes Macrovipera lebetina subspecies. Toxicon 2019;158:16–32. DOI: https://doi.org/10.1016/j.toxicon.2018.11.294
  57. Tourki B, Dumesnil A, Belaidi E, et al. Lebetin 2, a snakevenom-derived B-type natriuretic peptide, provides immediate and prolonged protection against myocardial ischemia-reperfusion injury via modulation of post-ischemic inflammatory response. Toxins 2019;11:524. DOI: https://doi.org/10.3390/toxins11090524
  58. Bouzazi D, Mami W, Mosbah A, et al. Natriuretic-like peptide Lebetin 2 mediates M2 macrophage polarization in LPS-activated RAW264.7 cells in an IL-10-dependent manner. Toxins 2023;15:298. DOI: https://doi.org/10.3390/toxins15040298
  59. Messadi E. Snake venom components as therapeutic drugs in ischemic heart disease. Biomolecules 2023;13:1539. DOI: https://doi.org/10.3390/biom13101539
  60. Diochot S, Baron A, Salinas M, et al. Black mamba venom peptides target acid-sensing ion channels to abolish pain. Nature 2012;490:552–5. DOI: https://doi.org/10.1038/nature11494
  61. Tourki B, Matéo P, Morand J, et al. Lebetin 2, a snake venom-derived natriuretic peptide, attenuates acute myocardial ischemic injury through the modulation of mitochondrial permeability transition pore at the time of reperfusion. PLoS One 2016;11:e0162632. DOI: https://doi.org/10.1371/journal.pone.0162632

Metrics

Citations and online attention from Dimensions, Altmetric and PlumX.