Detoxification of Peptide-Containing Biotoxins
https://doi.org/10.35825/2587-5728-2023-8-3-256-269
EDN: jokpyt
Abstract
Highlights. Peptide biotoxins are important problem for human health and as lethal agents due to their wild diversity of chemical structures and biological sources.
Such peptide biotoxins and prion proteins can be effectively neutralized by different methods, including by protease treatment.
Relevance – biological toxins containing peptides possess serious danger for life and well being of humans. There are a lot of reviews summarizing immunologic protective measures against these toxins. As opposed to that an enzymatic detoxification of biotoxins is, at best, considered superficially.
The purpose of the work is analysis of the main up-to-date trends of development of protective remedies against biotoxins of peptide nature.
The source base of the research is mainly English–language scientific literature available via the global Internet network, as well as the authors' own published experimental studies.
The research method is analytical.
Results. Currently the efficiency of detoxifying immunological drugs is surging due to highly productive methods of screening and selection of effective clones producing monoclonal antibodies. Special attention in the review is paid to application of hydrolytic enzymes which are considered in the work as alternative for immunobiological agents during detoxication of peptide biotoxins. The natural analogue of detoxifying enzymes is a system “toxin–antitoxin” of procaryotes. More than four types of inhibitors of biotoxins are know: blocking of their catalytic activity; hindering of their target receptors; inhibiting of toxin by acting on its structure; and allosterically modulating of biotoxin activity. There are encouraging data on application of detoxifying enzymes for neutralization of prions in soils and for treatment of prion complication.
Conclusions. Application of proteases for detoxification of peptide biotoxins and prion peptides could be considered as viable alternative to detoxifying immunobiological agents.
About the Authors
Ilya V. LyaginRussian Federation
Ilya V. Lyagin. Senior Researcher, Cand Sci (Chem). Grant team member.
Lenin Hills, 1/3, Moscow 119991;
Kosygin Str., 4, Moscow 119334.
Olga V. Maslova
Russian Federation
Olga V. Maslova. Senior Researcher, Cand Sci (Chem). Grant team member.
Lenin Hills, 1/3, Moscow 119991.
Olga V. Senko
Russian Federation
Olga V. Senko. Researcher, Cand Sci (Chem). Grant team member.
Lenin Hills, 1/3, Moscow 119991;
Kosygin Str., 4, Moscow 119334.
Nikolay A. Stepanov
Russian Federation
Nikolay A. Stepanov. Researcher, Cand. Sci. (Techn.). Grant team member.
Lenin Hills, 1/3, Moscow 119991;
Kosygin Str., 4, Moscow 119334.
Elena N. Efremenko
Russian Federation
Elena N. Efremenko. Laboratory Chief. Dr Sci. (Biol.). Professor. Grant team member.
Lenin Hills, 1/3, Moscow 119991;
Kosygin Str., 4, Moscow 119334.
References
1. Clark GC, Casewell NR, Elliott CT, Harvey AL, Jamieson AG, Strong PN, et al. Friends or foes? Emerging impacts of biological toxins. Trends Biochem Sci. 2019;44(4):365–79. https://doi.org/10.1016/j.tibs.2018.12.004
2. Efremenko E, Aslanli A, Lyagin I. Advanced situation with recombinant toxins: Diversity, production and application purposes. Int J Mo. Sci. 2023;24(5):4630. https://doi.org/10.3390/ijms24054630
3. Супотницкий МВ. Биологические свойства бактериальных токсинов. Вестник войск РХБ защиты. 2024;8(1):34–64. EDN: jtrfxo https://doi.org/10.35825/2587-5728-2024-8-1-34-64 [Supotnitskiy MV. The Biological properties of bacterial toxins. Journal of NBC Protection Corps. 2024;8(1):34–64. EDN:jtrfxo https://doi.org/10.35825/2587-5728-2024-8-1-34-64]
4. Osipov A, Utkin Y. What are the neurotoxins in hemotoxic snake venoms? Int J Mol Sci. 2023;24(3):2919. https://doi.org/10.3390/ijms24032919
5. Page R, Peti W. Toxin–antitoxin systems in bacterial growth arrest and persistence. Nat Chem Biol. 2016;12(4):208–14. https://doi.org/10.1038/nchembio.2044
6. Andryukov BG, Somova LM, Timchenko NF, Bynina MP, Lyapun IN. Toxin–antitoxin systems and their role in maintaining the pathogenic potential of causative agents of Sapronoses. Infect Disord Drug Targets. 2020;20(5):570–84. https://doi.org/10.2174/1871526519666190715150444
7. Gutiérrez JM, Albulescu LO, Clare RH, Casewell NR, Abd El-Aziz TM, Escalante T, et al. The search for natural and synthetic inhibitors that would complement antivenoms as therapeutics for snakebite envenoming. Toxins. 2021;13(7):451. https://doi.org/10.3390/toxins13070451
8. Wang X, Xia Z, Wang H, Wang D, Sun T, Hossain E, et al. Cell-membrane-coated nanoparticles for the fight against pathogenic bacteria, toxins, and inflammatory cytokines associated with sepsis. Theranostics. 2023;13(10):3224–44. https://doi.org/10.7150/thno.81520
9. Romero-Giraldo LE, Pulido S, Berrío MA, Flórez MF, Rey-Suárez P, Nuñez V, et al. Heterologous expression and immunogenic potential of the most abundant phospholipase a2 from coral snake Micrurus dumerilii to develop antivenoms. Toxins. 2022;14(12):825. https://doi.org/10.3390/toxins14120825
10. Ryabchevskaya EM, Granovskiy DL, Evtushenko EA, Ivanov PA, Kondakova OA, Nikitin NA, et al. Designing stable Bacillus anthracis antigens with a view to recombinant anthrax vaccine development. Pharmaceutics. 2022;14(4):806. https://doi.org/10.3390/pharmaceutics14040806
11. Granovskiy DL, Ryabchevskaya EM, Evtushenko EA, Kondakova OA, Arkhipenko MV, Kravchenko TB, et al. New formulation of a recombinant anthrax vaccine stabilised with structurally modified plant viruses. Front Microbiol. 2022;13:1003969. https://doi.org/10.3389/fmicb.2022.1003969
12. Karpov DS, Goncharenko AV, Usachev EV, Vasina DV, Divisenko EV, Chalenko YM, et al. A Strategy for the Rapid Development of a Safe Vibrio cholerae Candidate Vaccine Strain. Int J Mol Sci. 2021;22(21):11657. https://doi.org/10.3390/ijms222111657
13. Rudenko N, Nagel A, Zamyatina A, Karatovskaya A, Salyamov V, Andreeva-Kovalevskaya Z, et al. A monoclonal antibody against the C-terminal domain of Bacillus cereus hemolysin II inhibits HlyII cytolytic activity. Toxins. 2020;12(12):806. https://doi.org/10.3390/toxins12120806
14. Abramov VM, Kosarev IV, Motin VL, Khlebnikov VS, Vasilenko RN, Sakulin VK, et al. Binding of LcrV protein from Yersinia pestis to human T-cells induces apoptosis, which is completely blocked by specific antibodies. Int J Biol Macromol. 2019;122:1062–70. https://doi.org/10.1016/j.ijbiomac.2018.09.054
15. Godakova SA, Noskov AN, Vinogradova ID, Ugriumova GA, Solovyev AI, Esmagambetov IB, et al. Camelid VHHs Fused to Human Fc Fragments Provide Long Term Protection Against Botulinum Neurotoxin A in Mice. Toxins. 2019;11(8):464. https://doi.org/10.3390/toxins11080464
16. Yu X, Gao X, Zhu K, Yin H, Mao X, Wojdyla JA, et al. Characterization of a toxin-antitoxin system in Mycobacterium tuberculosis suggests neutralization by phosphorylation as the antitoxicity mechanism. Commun Biol. 2020;3(1):216. https://doi.org/10.1038/s42003-020-0941-1
17. Yao J, Zhen X, Tang K, Liu T, Xu X, Chen Z, et al. Novel polyadenylylation-dependent neutralization mechanism of the HEPN/MNT toxin/antitoxin system. Nucleic Acids Res. 2020;48(19):11054–67. https://doi.org/10.1093/nar/gkaa855
18. Wang X, Lord DM, Cheng HY, Osbourne DO, Hong SH, Sanchez-Torres V, et al. A new type V toxinantitoxin system where mRNA for toxin GhoT is cleaved by antitoxin GhoS. Nat Chem Biol. 2012;8(10):855–61. https://doi.org/10.1038/nchembio.1062
19. Marimon O, Teixeira JM, Cordeiro TN, Soo VW, Wood TL, Mayzel M, et al. An oxygen-sensitive toxinantitoxin system. Nat Commun. 2016;7:13634. https://doi.org/10.1038/ncomms13634
20. Jankevicius G, Ariza A, Ahel M, Ahel I. The toxin-antitoxin system DarTG catalyzes reversible ADP-ribosylation of DNA. Mol Cell. 2016;64(6):1109–16. https://doi.org/10.1016/j.molcel.2016.11.014
21. Albulescu L-O, Xie C, Ainsworth S, Alsolaiss J, Crittenden E, Dawson CA, et al. A therapeutic combination of two small molecule toxin inhibitors provides broad preclinical efficacy against viper snakebite. Nat Commun. 2020;11(1):6094. https://doi.org/10.1038/s41467-020-19981-6
22. Guo Z, Yue N, Chen M, Li J, Lv R, Wang J, et al. Purinergic Receptor Antagonists Inhibit Hemolysis Induced by Clostridium perfringens Alpha Toxin. Pathogens. 2024;13(6):454. https://doi.org/10.3390/pathogens13060454
23. Yermak IM, Volod’ko AV, Khasina EI, Davydova VN, Chusovitin EA, Goroshko DL, et al. Inhibitory Effects of Carrageenans on Endotoxin-Induced Inflammation. Mar Drugs. 2020;18(5):248. https://doi.org/10.3390/md18050248
24. Patel KB, Kononova O, Cai S, Barsegov V, Parmar VS, Kumar R, et al. Botulinum neurotoxin inhibitor binding dynamics and kinetics relevant for drug design. Biochim Biophys Acta Gen Subj. 2021;1865(9):129933. https://doi.org/10.1016/j.bbagen.2021.129933
25. Yang Z, Wang C, Liu J, Xiao L, Guo L, Xie J. In Silico–Ex Vitro Iteration Strategy for Affinity Maturation of Anti-Ricin Peptides and the SPR Biosensing Application. Toxins. 2023;15(8):490. https://doi.org/10.3390/toxins15080490
26. Aziz UBA, Saoud A, Bermudez M, Mieth M, Atef A, Rudolf T, et al. Targeted small molecule inhibitors blocking the cytolytic effects of pneumolysin and homologous toxins. Nat Commun. 2024;15(1):3537. https://doi.org/10.1038/s41467-024-47741-3
27. Lin L, Olson ME, Sugane T, Turner LD, Tararina MA, Nielsen AL, et al. Catch and Anchor Approach To Combat Both Toxicity and Longevity of Botulinum Toxin A. J Med Chem. 2020;63(19):11100–20. https://doi.org/10.1021/acs.jmedchem.0c01006
28. Desai N, Pande S, Salave S, Singh TRR, Vora LK. Antitoxin nanoparticles: design considerations, functional mechanisms, and applications in toxin neutralization. Drug Discov Today. 2024;29(8):104060. https://doi.org/10.1016/j.drudis.2024.104060
29. Ефременко ЕН, Лягин ИВ, Маслова ОВ, Сенько ОВ, Степанов НА, Асланлы АГ. Каталитическое разложение микропластиков. Успехи химии. 2023;92(2):RCR5069. https://doi.org/10.57634/RCR5069 [Efremenko EN, Lyagin IV, Maslova OV, Senko OV, Stepanov NA, Aslanli AG. Catalytic degradation of microplastics. Russ Chem Rev. 2023;92(2):RCR5069. https://doi.org/10.57634/RCR5069]
30. Маслова ОВ, Сенько ОВ, Степанов НА, Лягин ИВ, Ефременко ЕН. Биокатализ в деградации синтетических полимеров. Вестник Московского университета. Серия 2: Химия. 2024;65(2):161–8. https://doi.org/10.55959/MSU0579-9384-2-2024-65-2-161-168 [Maslova OV, Senko OV, Stepanov NA, Lyagin IV, Efremenko EN. Biocatalysis in the Degradation of Synthetic Polymers. Moscow Univ Chem Bull. 2024;79(2):140–5. https://doi.org/10.3103/S0027131424700019]
31. Wang D, Pan Q, Yang J, Gong S, Liu X, Fu Y. Effects of Mixtures of Engineered Nanoparticles and Cocontaminants on Anaerobic Digestion. Environ. Sci Technol. 2024;58(6):2598–2614. https://doi.org/10.1021/acs.est.3c09239
32. Wei L, Li J, Wang Z, Wu J, Wang S, Cai Z, et al. Evaluating effects of tetrabromobisphenol A and microplastics on anaerobic granular sludge: Physicochemical properties, microbial metabolism, and underlying mechanisms. J Environ Manage. 2024;359:121077. https://doi.org/10.1016/j.jenvman.2024.121077
33. Samel M, Vija H, Kurvet I, Künnis-Beres K, Trummal K, Subbi J, et al. Interactions of PLA2-s from Vipera lebetina, Vipera berus berus and Naja naja oxiana venom with platelets, bacterial and cancer cells. Toxins. 2013;5(2):203–23. https://doi.org/10.3390/toxins5020203
34. Barr JR, Moura H, Boyer AE, Woolfitt AR, Kalb SR, Pavlopoulos A, et al. Botulinum neurotoxin detection and differentiation by mass spectrometry. Emerg Infect Dis. 2005;11(10):1578–83. https://doi.org/10.3201/eid1110.041279
35. Kalb SR, Baudys J, Wang D, Barr JR. Recommended mass spectrometry-based strategies to identify botulinum neurotoxin-containing samples. Toxins. 2015;7(5):1765–78. https://doi.org/10.3390/toxins7051765
36. Dupré M, Gilquin B, Fenaille F, Feraudet-Tarisse C, Dano J, Ferro M, et al. Multiplex quantification of protein toxins in human biofluids and food matrices using immunoextraction and high-resolution targeted mass spectrometry. Anal Chem. 2015;87(16):8473–80. https://doi.org/10.1021/acs.analchem.5b01900
37. Alam SI, Kumar B, Kamboj DV. Multiplex detection of protein toxins using MALDI-TOF-TOF tandem mass spectrometry: application in unambiguous toxin detection from bioaerosol. Anal Chem. 2012;84(23):10500–07. https://doi.org/10.1021/ac3028678
38. Mirgorodskaya OA, Kazanina GA, Mirgorodskaya EP, Vorotyntseva TI, Zamolodchikova TS, Alexandrov SL. A Comparative study of the specificity of melittin hydrolysis by duodenase, trypsin and plasmin. Prot Pept Lett. 1996;3(5):315–20.
39. Sokolova EA, Mirgorodskaya OA, Roepstorff P, Savelyeva NV, Zamolodchikova TS. Comparative study of the action of bovine duodenal proteinases (duodenases) on polypeptide substrates. Biochemistry (Mosc). 2001;66(1):62–7. https://doi.org/10.1023/a:1002833729744
40. Mirgorodskaya O, Kazanina G, Mirgorodskaya E, Matveyev V, Thiede B, Khaitlina S. Proteolytic cleavage of melittin with the actin-digesting protease. Prot Pept Lett. 1996;3(2):81–8.
41. El-Didamony SE, Kalaba MH, Sharaf MH, El-Fakharany EM, Osman A, Sitohy M, et al. Melittin alcalasehydrolysate: a novel chemically characterized multifunctional bioagent; antibacterial, anti-biofilm and anticancer. Front Microbiol. 2024;15:e1419917. https://doi.org/10.3389/fmicb.2024.1419917
42. Lee H-S, Kim YS, Lee K-S, Seo H-S, Lee C-Y, Kim KK. Detoxification of Bee Venom Increases Its Anti-inflammatory Activity and Decreases Its Cytotoxicity and Allergenic Activity. Appl Biochem Biotechnol. 2021;193(12):4068–82. https://doi.org/10.1007/s12010-021-03653-2
43. Galli SJ, Metz M, Starkl P, Marichal T, Tsai M. Mast cells and IgE in defense against lethality of venoms: Possible “benefit” of allergy. Allergo J Int. 2020;29(2):46–62. https://doi.org/10.1007/s40629-020-00118-6
44. Hellman L, Akula S, Fu Z, Wernersson S. Mast Cell and Basophil Granule Proteases - In Vivo Targets and Function. Front Immunol. 2022;13:918305 https://doi.org/10.3389/fimmu.2022.918305
45. Anderson E, Stavenhagen K, Kolarich D, Sommerhoff CP, Maurer M, Metz M. Human Mast Cell Tryptase Is a Potential Treatment for Snakebite Envenoming Across Multiple Snake Species. Front Immunol. 2018;9:1532. https://doi.org/10.3389/fimmu.2018.01532
46. Xu Q, Ma H, Zhang H, Fan J, Yin C, Liu X, et al. Purification and activity of the first recombinant enzyme for biodegrading hepatotoxin by Sphingopyxis sp. USTB-05. Algal Res. 2020;47:101863. https://doi.org/10.1016/j.algal.2020.101863
47. Zou Q, Teng J, Wang K, Huang Y, Hu Q, Chen S, et al. Purification and mechanism of microcystinase MlrC for catalyzing linearized cyanobacterial hepatotoxins using Sphingopyxis sp. USTB-05. Toxins. 2022;14(9):602. https://doi.org/10.3390/toxins14090602
48. Teng J, Song M, Xu Q, Zou Q, Zhang H, Yin C, et al. Purification and activity of the second recombinant enzyme for biodegrading linearized microcystins by Sphingopyxis sp. USTB-05. Toxins. 2023;15(8):494. https://doi.org/10.3390/toxins15080494
49. Wu X, Wu H, Gu X, Zhang R, Sheng Q, Ye J. Effect of the immobilized microcystin-LR-degrading enzyme MlrA on nodularin degradation and its immunotoxicity study. Environ Pollut. 2020;258:113653. https://doi.org/10.1016/j.envpol.2019.113653
50. Johnson CJ, Bennett JP, Biro SM, Duque-Velasquez JC, Rodriguez CM, Bessen RA, et al. Degradation of the disease-associated prion protein by a serine protease from lichens. PLoS One. 2011;6(5):19836. https://doi.org/10.1371/journal.pone.0019836
51. Saunders SE, Bartz JC, Vercauteren KC, Bartelt-Hunt SL. Enzymatic digestion of chronic wasting disease prions bound to soil. Environ Sci Technol. 2010;44(11):4129–35. https://doi.org/10.1021/es903520d
52. Langeveld JPM, Wang J-J, Van de Wiel DFM, Shih GC, Garssen GJ, Bossers A, et al. Enzymatic degradation of prion protein in brain stem from infected cattle and sheep. J Infect Dis. 2003;188(11):1782–9. https://doi.org/10.1086/379664
53. Pilon JL, Nash PB, Arver T, Hoglund D, VerCauteren KC. Feasibility of infectious prion digestion using mild conditions and commercial subtilisin. J Virol Methods. 2009;161(1):168–72. https://doi.org/10.1016/j.jviromet.2009.04.040
54. Hsu RL, Lee KT, Wang JH, Lee LY, Chen RP. Amyloid-degrading ability of nattokinase from Bacillus subtilis natto. J Agric Food Chem. 2009;57(2):503–8. https://doi.org/10.1021/jf803072r
55. Lampe BJ, English JC. Toxicological assessment of nattokinase derived from Bacillus subtilis var. natto. Food Chem Toxicol. 2016;88:87–99. https://doi.org/10.1016/j.fct.2015.12.025
56. Naik S, Katariya R, Shelke S, Patravale V, Umekar M, Kotagale N, et al. Nattokinase prevents β-amyloid peptide (Aβ1-42) induced neuropsychiatric complications, neuroinflammation and BDNF signalling disruption in mice. Eur J Pharmacol. 2023;952:175821. https://doi.org/10.1016/j.ejphar.2023.175821
57. Chen H, McGowan EM, Ren N, Lal S, Nassif N, Shad-Kaneez F, et al. Nattokinase: A Promising Alternative in Prevention and Treatment of Cardiovascular Diseases. Biomark. Insights. 2018;13:1177271918785130. https://doi.org/10.1177/1177271918785130
58. Hulscher N, Procter BC, Wynn C, McCullough PA. Clinical Approach to Post-acute Sequelae After COVID19 Infection and Vaccination. Cureus. 2023;15(11):e49204. https://doi.org/10.7759/cureus.49204
59. Parry PI, Lefringhausen A, Turni C, Neil CJ, Cosford R, Hudson NJ, Gillespie J. ‘Spikeopathy’: COVID-19 Spike Protein Is Pathogenic, from Both Virus and Vaccine mRNA. Biomedicines. 2023;11:2287. https://doi.org/10.3390/biomedicines11082287
60. Jack K, Jackson GS, Bieschke J. Essential components of synthetic infectious prion formation de novo. Biomolecules. 2022;12(11):1694. https://doi.org/10.3390/biom12111694
61. You Y, Suraj HM, Matz L, Valderrama ALH, Ruigrok P, Shi-Kunne X, et al. Botrytis cinerea combines four molecular strategies to tolerate membrane-permeating plant compounds and to increase virulence. Nat Commun. 2024;15(1):6448. https://doi.org/10.1038/s41467-024-50748-5
62. Efremenko E, Lyagin I, Stepanov N, Senko O, Maslova O, Aslanli A, et al. Luminescent Bacteria as Bioindicators in Screening and Selection of Enzymes Detoxifying Various Mycotoxins. Sensors. 2024;24(3):763. https://doi.org/10.3390/s24030763
63. Roy S, Srinivasan VR, Arunagiri S, Mishra N, Bhatia A, Shejale KP, et al. Molecular insights into the phase transition of lysozyme into amyloid nanostructures: Implications of therapeutic strategies in diverse pathological conditions. Adv Colloid Interface Sci. 2024;331:103205. https://doi.org/10.1016/j.cis.2024.103205
Review
For citations:
Lyagin I.V., Maslova O.V., Senko O.V., Stepanov N.A., Efremenko E.N. Detoxification of Peptide-Containing Biotoxins. Journal of NBC Protection Corps. 2024;8(3):256-269. (In Russ.) https://doi.org/10.35825/2587-5728-2023-8-3-256-269. EDN: jokpyt