- PII
- 10.31857/S0869769824030064-1
- DOI
- 10.31857/S0869769824030064
- Publication type
- Review
- Status
- Published
- Authors
- Volume/ Edition
- Volume / Issue number 3
- Pages
- 101-120
- Abstract
- The review briefly describes a research carried out over the past 40 years at the Laboratory of Peptide Chemistry of G.B. Elyakov Pacific Institute of Bioorganic Chemistry, FEB RAS (LPCh of PIBOC FEB RAS), in collaboration with Russian and foreign colleagues. The results of search, identification, and study of the structure, the biological activity, and the mechanisms of an interaction with the biological targets of peptides and polypeptides produced by the tropical sea anemone Heteractis crispa (=Heteractis magnifica, formerly Radianthus macrodactylus) are discussed. One of the main achievements of LPCh over the past years is the discovery of new structural type 2 neurotoxins, namely, six toxins that were not identified among the representatives of so-called long anemonotoxins in the first decade of foreign research (70–80s of the last century), and among them the first, previously unknown, double-chain neurotoxin. In addition, the presence of several multigene families expressing α-pore-forming toxins (actinoporins), serine protease inhibitors (Kunitz-type peptides), and APETx-like peptides forming the combinatorial libraries of the several dozen of highly homologous family members has been established. Using in silico methods (homologous modeling, alanine mutagenesis, full-atom molecular dynamics (MD) simulation), the spatial structures of the studied peptides and complexes with biological targets were predicted for the first time, and their structure-functional relationships were analyzed. This was the foundation for the further production of recombinant and mutant analogues on the basis of the combinatorial libraries for the purpose of conducting the electrophysiological studies of the mechanisms of their molecular interaction with targets as well as determining the pharmacological potential. In the review the most important results of recent years are presented. They are related to the discovery of analgesic, anti-inflammatory, and antitumor activity in a number of the studied peptides.
- Keywords
- морские анемоны нейротоксины пептиды Кунитц-типа APETx-подобные пептиды дефензины биологические мишени
- Date of publication
- 15.09.2025
- Year of publication
- 2025
- Number of purchasers
- 0
- Views
- 11
References
- 1. Prentis P. J., Pavasovic A., Norton R. S. Sea anemones: quiet achievers in the field of peptide toxins // Toxins. 2018. Vol. 10. P. 36. https://doi.org/10.3390/toxins10010036.
- 2. Béress L. Biologically active compounds from coelenterates // Pure Appl. Chem. 1982. Vol. 54. P. 1981–1994. https://doi.org/10.1016/0014-5793 (75)80517-5.
- 3. Norton R. S. Structure and structure-function relationships of sea anemone proteins that interact with the sodium channel // Toxicon. 1991. Vol. 29. P. 1051–1084. https://doi.org/10.1016/0041-0101 (91)90205-6.
- 4. Zykova T. A., Vinokurov L. M., Kozlovskaya E. P., Elyakov G. B. Amino acid sequence of neurotoxin III from the sea anemone Radianthus macrodactylus // Bioorg. Khim. 1985. Vol. 11. P. 302–310.
- 5. Zykova T. A., Kozlovskaya E. P. Amino acid sequence of a neurotoxin from the sea anemone Radianthus macrodactylus // Bioorg. Khim. 1989. Vol. 15. P. 1301–1306.
- 6. Zykova T. A., Kozlovskaya E. P., Elyakov G. B. Amino acid sequence of neurotoxin II from the sea anemone Radianthus macrodactylus // Bioorg. Khim. 1988. Vol. 14. P. 878–882.
- 7. Zykova T. A., Kozlovskaya E. P., Elyakov G. B. Amino acid sequence of neurotoxins IV and V from the sea anemone Radianthus macrodactylus // Bioorg. Khim. 1988. Vol. 14. P. 1489–1494.
- 8. Monastyrnaya M. M., Kalina R. S. Kozlovskaya E. P. The sea anemone neurotoxins modulating sodium channels: an insight at structure and functional activity after four decades of investigation // Toxins. 2023. Vol. 15. P. 8. https://doi.org/10.3390/toxins15010008.
- 9. Schweitz H., Bidard J. N., Frelin C., Pauron D., Vijverberg H. P.M., Mahasneh D. M., Lazdunski M., Vibois F., Tsugita A. Purification, sequence, and pharmacological properties of sea anemone toxins from Radianthus paumotensis. A new class of sea anemone toxins acting on the sodium channel // Biochemistry. 1985. Vol. 24. P. 3554–3561. https://doi.org/10.1021/bi00335a025.
- 10. Honma T., Kawahata S., Ishida M., Nagai H., Nagashima Y., Shiomi K. Novel peptide toxins from the sea anemone Stichodactyla haddoni // Peptides. 2008. Vol. 29. P. 536–544. https://doi.org/10.1016/j.peptides.2007.12.010.
- 11. Kem W. R., Parten B., Pennington M. W., Price D. A., Dunn B. M. Isolation, characterization, and amino acid sequence of a polypeptide neurotoxin occurring in the sea anemone Stichodactyla helianthus // Biochemistry. 1989. Vol. 28. P. 3483–3489. https://doi: 968 10.1021/bi00434a050.
- 12. Wunderer G., Fritz H., Wachter E., Machleidt W. Amino acid sequence of a coelenterate toxin: Toxin II from Anemonia sulcata // Eur. J. Biochem. 1976. Vol. 8. P. 193–198. https://doi: 10.1111/j.1432-1033.1976.tb10778.x.
- 13. Tanaka M., Hainu M., Yasunobu K. T., Norton T. R. Amino acid sequence of the Anthopleura xanthogrammica heart stimulant anthopleurin-A // Biochemistry. 1977. Vol. 16. 204–208. https://doi: 10.1021/bi00621a007.
- 14. Reimer N. S., Yasunobu C. L., Yasunobu K. T., Norton T. R. Amino acid sequence of the Anthopleura xanthogrammica heart stimulant, anthopleurin B // J. Biol. Chem. 1985. Vol. 260. P. 8690–8693.
- 15. Kalina R. S., Peigneur S., Zelepuga E. A., Dmitrenok P. S., Kvetkina A. N., Kim N. Y., Leychenko E. V., Tytgat J., Kozlovskaya E. P., Monastyrnaya M. M., Gladkikh I. N. New insights into the type II toxins from the sea anemone Heteractis crispa // Toxins. 2020. Vol. 12. P. 44. https://doi.org/10.3390/toxins12010044.
- 16. Baydan L. V., Kozlovskaya E. P., Tishkin S. M., Shuba M. F., Elyakov G. B. Effect of anemonotoxin on neuromuscular transmission in skeletal and smooth muscles // Dokl. Acad. Sci. USSR. 1981. Vol. 259. P. 1000–1002.
- 17. Sorokina Z. A., Chizhmakov I. V., Elyakov G. B., Kozlovskaya E. P., Vozhzhova E. I. Investigation of inactivation mechanism of fast sodium channels using neurotoxin from the sea anemone Radianthus macrodactylus and various chemical reagents // Physiol. J. 1984. Vol. 30. P. 571–579.
- 18. Linder R., Bernheimer A. W., Kim K. S. Interaction between sphingomyelin and a cytolysin from the sea anemone Stoichactis helianthus // Biochim. Biophys. Acta. 1977. Vol. 467, N3. P. 290–300.
- 19. Varanda W., Finkelstein A. Ion and nonelectrolyte permeability properties of channels formed in planar lipid bilayer membranes by the cytolytic toxin from the sea anemone, Stoichactis helianthus // J. Membr. Biol. 1980. Vol. 55, N3. P. 203–211.
- 20. Чантурия А. Н., Шатурский О. Я., Лишко В. К., Монастырная М. М., Козловская Э. П. Взаимодействие токсина морской актинии Radianthus macrodactylus с бислойными фосфолипидными мембранами // Биол. мембраны. 1990. Т. 7, № 7. С. 763–769.
- 21. Monastyrnaya M. M., Zykova T. A., Apalikova O. V., Shwets T. V., Kozlovskaya E. P. Biologically active polypeptides from the tropical sea anemone Radianthus macrodactylus // Toxicon. 2002. Vol. 40. P. 1197–1217. https://doi: 10.1016/s0041-0101(02)00139-3.
- 22. Ильина А. П., Монастырная М. М., Сокотун И. Н., Егоров Ц. А., Назаренко Ю. А., Лихацкая Г. Н. Актинопорины из актинии Японского моря Oulactis orientalis: выделение и частичная характеристика // Биоорган. химия. 2005. Т. 31, № 1. C. 39–48.
- 23. Klyshko E. V., Issaeva M. P., Monastyrnaya M. M., Il’ina A.P., Guzev K. V., Vakorina T. I., Dmitrenok P. S., Zykova T. A., Kozlovskaya E. P. Isolation, properties and partial amino acid sequence of a new actinoporin from the sea anemone Radianthus macrodactylus // Toxicon. 2004. Vol. 44. P. 315–324. https://doi: 10.1016/j.toxicon.2004.06.006.
- 24. Monastyrnaya M., Leychenko E., Issaeva M., Likhatskaya G., Zelepuga E., Kostina E., Trifonov E., Nurminski E., Kozlovskaya E. Actinoporins from the sea anemones, tropical Radianthus macrodactylus and northern Oulactis orientalis: Comparative analysis of structure-function relationships // Toxicon. 2010. Vol. 56. P. 1299–1314. https://doi: 10.1016/j.toxicon.2010.07.011.
- 25. Ильина А. П., Монастырная М. М., Исаева М. П., Гузев К. В., Рассказов В. А., Козловская Э. П. Первичная структура актинопоринов актинии Oulactis orientalis // Биоорган. химия. 2005. Т. 31, № 4. C. 357–362.
- 26. Il’ina A., Lipkin A., Barsova E., Issaeva M., Leychenko E., Guzev K., Monastyrnaya M., Lukyanov S., Kozlovskaya E. Amino acid sequence of RTX-A’s isoform actinoporin from the sea anemone Radianthus macrodactylus // Toxicon. 2006. Vol. 47. P. 517–520. https://doi: 10.1016/j.toxicon.2005.12.014.
- 27. Leychenko E., Isaeva M., Tkacheva E., Zelepuga E., Kvetkina A., Gusev K., Monastyrnaya M., Kozlovskaya E. Multigene family of pore-forming toxins from sea anemone Heteractis crispa // Mar. Drugs. 2018. Vol. 16. 183 [1−18]. https://doi.org/10.3390/md16060183.
- 28. Иванов А. С., Мольнар А. А., Монастырная М. М., Козловская Э. П. Действие токсина из Radianthus macrodactylus на проницаемость биологических и модельных мембран // Биол. мембраны. 1987. Т. 4, № 3. С. 243–248.
- 29. Козловская Э. П., Иванов А. С., Мольнар А. А., Григорьев П. А., Монастырная М. М., Халилов Э. М., Еляков Г. Б. Ионные каналы в мембранах, индуцированные гемолизином из актинии Radianthus macrodactylus // Докл. АН СССР. 1984. Т. 277, № 6. С. 1491–1493.
- 30. Bakrač B., Gutiérrez-Aguirre I., Podlesek Z., Sonnen A. F.-P., Gilbert R. J.C., Maček P., Lakey J. H., Anderluh G. Molecular determinants of sphingomyelin specificity of a eukaryotic pore-forming toxin // J. Biol. Chem. 2008. Vol. 283. P. 18665–18677. https://doi: 10.1074/jbc.M708747200.
- 31. Mechaly A. E., Bellomio A., Gil-Carton D., Morante K., Valle M., González-Mañas J.M., Guérin D. M. Structural insights into the oligomerization and architecture of eukaryotic membrane pore-forming toxins // Structure. 2011. Vol. 19. P. 181–191. https://doi: 10.1016/j.str.2010.11.013.
- 32. Bellomio A., Morante K., Barlič A., Gutiérrez-Aguirre I., Viguera A. R., González-Mañas J. M. Purification, cloning and characterization of fragaceatoxin C, a novel actinoporin from the sea anemone Actinia fragacea // Toxicon. 2009. Vol. 54. P. 869–880. https://doi: 10.1016/j.toxicon.2009.06.022.
- 33. Mancheño J. M., Martin-Benito J., Martínez M., Gavilanes J. G., Hermoso J. A. Crystal and electron microscopy structures of Sticholysin II actinoporin reveal insights into the mechanism of membrane pore formation // Structure. 2003. Vol. 11. P. 1–20. https://doi: 10.1016/j.str.2003.09.019.
- 34. Руднев В. С., Лихацкая Г. Н., Козловская Э. П., Монастырная М. М., Еляков Г. Б. Влияние гемолизина из морской актинии Radianthus macrodactylus на проницаемость липидных мембран // Биол. мембраны. 1984. Т. 1, № 10. С. 1019–1023.
- 35. Fedorov S., Dyshlovoy S., Monastyrnaya M., Shubina L., Leychenko E., Kozlovskaya E., Jin J. O., Kwak J. Y., Bode A. M., Dong Z., Stonik V. The anticancer effects of actinoporin RTX-A from the sea anemone Heteractis crispa (=Radianthus macrodactylus) // Toxicon. 2010. Vol. 55. P. 811–817. https://doi: 10.1016/j.toxicon.2009.11.016.
- 36. Kvetkina A., Malyarenko O., Pavlenko A., Dyshlovoy S., von Amsberg G., Ermakova S., Leychenko E. Sea anemone Heteractis crispa actinoporin demonstrates in vitro anticancer activities and prevents HT-29 colorectal cancer cell migration // Molecules. 2020. Vol. 25. 5979. https://doi: 10.3390/molecules25245979.
- 37. Брежестовский П. Д., Монастырная М. М., Козловская Э. П., Еляков Г. Б. Действие гемолизина из морской актинии Radianthus macrodactylus на мембрану эритроцитов // Докл. АН СССР. 1988. Т. 299, № 3. С. 748–750.
- 38. Leichenko E. V., Monastirnaya M. M., Zelepuga E. A., Tkacheva E. S., Isaeva M. P., Likhatskaya G. N., Anastyuk S. D., Kozlovskaya E. P. Hct-A is a new actinoporin family from the Heteractis crispa sea anemone // Acta Naturae. 2014. Vol. 6. P. 89–98.
- 39. Monastyrnaya M. M., Agafonova I. G., Tabakmakher V. M., Kozlovskaya E. P. The sea anemone pore-forming toxins (PFTs): from mechanism of action to perspectives in pharmacology as antitumor agents // EC Pharmacol. and Toxicol. 2023. Vol. 11, N4. P. 20–26. DOI: 10.31080/ecpt.2023.11.00829.
- 40. Shnyrov V. L., Monastyrnaya M. M., Zhadan G. G., Kuznetsova S. M., Kozlovskaya E. P. Calorimetric study of interaction of toxin from Radianthus macrodactylus with erythrocyte membrane // Biochem. Intеrn. 1992. Vol. 26, N2. Р. 219–229.
- 41. Зыкова T. A., Винокуров Л. M., Mаркова Л. Ф., Koзловская Э. П., Еляков Г. Б. Аминокислотная последовательность ингибитора трипсина IV из Radianthus macrodactylus // Биоорг. химия. 1985. Т. 11. C. 293–301.
- 42. Isaeva M. P., Chausova V. E., Zelepuga E. A., Guzev K. V., Tabakmakher V. M., Monastyrnaya M. M., Kozlovskaya E. P. A new multigene superfamily of Kunitz-type protease inhibitors from sea anemone Heteractis crispa // Peptides. 2012. Vol. 34. P. 88–97. https://doi.org/ 10.1016/j.peptides.2011.09.022.
- 43. Kvetkina A., Leychenko E., Chausova V., Zelepuga E., Chernysheva N., Guzev K., Pislyagin E., Yurchenko E., Menchinskaya E., Aminin D., Kaluzhskiy L., Ivanov A., Peigneur S., Tytgat J., Kozlovskaya E. P., Isaeva M. P. A new multigene HCIQ subfamily from the sea anemone Heteractis crispa encodes Kunitz-peptides exhibiting neuroprotective activity against 6-hydroxydopamine // Scientific Reports. 2020. Vol. 10. P. 4205. https://doi: 10.1038/s41598-020-61034-x.
- 44. Сокотун И. Н., Гнеденко О. В., Лейченко Е. В., Монастырная М. М., Козловская Э. П., Мольнар А. А., Иванов А. С. Исследование взаимодействия ингибитора трипсина из актинии Radianthus macrodactylus с различными протеиназами // Биомед. химия. 2006. Т. 52, вып. 6. С. 595–600.
- 45. Gladkikh I., Monastyrnaya M., Leychenko E., Zelepuga E., Chausova V., Isaeva M., Anastyuk S., Andreev Y., Peigneur S., Tytgat J., Kozlovskaya E. Atypical reactive center Kunitz-type inhibitor from the sea anemone Heteractis crispa // Mar. Drugs. 2012. Vol. 10. P. 1545–1565. https://doi.org/ 10.3390/md10071545.
- 46. Gladkikh I., Monastyrnaya M., Zelepuga E., Sintsova O., Tabakmakher V., Gnedenko O., Ivanov A., Hua K.-F., Kozlovskaya E. New Kunitz-type HCRG polypeptides from the Sea anemone Heteractis crispa // Mar. Drugs. 2015. Vol. 13. P. 6038–6063. https://doi: 10.3390/md13106038.
- 47. Gladkikh I., Peigneur S., Sintsova O., Pinheiro-Junior E.L., Klimovich A., Menshov A., Kalinovsky A., Isaeva M., Monastyrnaya M., Kozlovskaya E., Tytgat J., Leychenko E. Kunitz-type peptides from the sea anemone Heteractis crispa demonstrate potassium channel blocking and anti-inflammatory activities // Biomedicines. 2020. Vol. 8. P. 473. https://doi.org/ 10.3390/biomedicines8110473.
- 48. Andreev Y. A., Kozlov S. A., Koshelev S. G., Ivanova E. A., Monastyrnaya M. M., Kozlovskaya E. P., Grishin E. V. Analgesic compound from sea anemone Heteractis crispa is the first polypeptide inhibitor of vanilloid receptor 1 (TRPV1) // J. Biol. Chem. 2008. Vol. 283. P. 23914–23921. https://doi.org/ 10.1074/jbc0.M800776200.
- 49. Monastyrnaya M., Peigneur S., Zelepuga E., Sintsova O., Gladkikh I., Leychenko E., Isaeva M., Tytgat J., Kozlovskaya E. Kunitz-type peptide HCRG21 from the sea anemone Heteractis crispa is a full peptide antagonist of the TRPV1 receptor // Mar. Drugs. 2016. Vol. 14. 229 [1–20]. https://doi.org/ 10.3390/md14120229.
- 50. Sintsova О. V., Monastyrnaya М. М., Pislyagin E. A., Menchinskaya E. S., Leychenko Е. V., Aminin D. L., Kozlovskaya E. P. Anti-inflammatory activity of the polypeptide of the sea anemone Heteractis crispa // Bioorg. Chem. 2015. Vol. 41. P. 590–596.
- 51. Sintsova O. V., Palikov V. A., Palikova Y. A., Klimovich A. A., Gladkikh I. N., Andreev Y. A., Monastyrnaya M. M., Kozlovskaya E. P., Dyachenko I. A., Kozlov S. A., Leychenko E. V. Peptide blocker of ion channel TRPV1 exhibits a long analgesic effect in the heat stimulation model // Dokl. Biochem. Biophys. 2020. Vol. 493. P. 215–217.
- 52. Sintsova О. V., Pislyagin E. A., Gladkikh I. N., Monastyrnaya М. М., Menchinskaya E. S., Leychenko Е. V., Aminin D. L., Kozlovskaya E. P. Kunitz-type peptides of the sea anemone Heteractis crispa – potential anti-inflammatory compounds // Bioorg. Chem. 2017. Vol. 43. P. 105–112.
- 53. Sintsova O., Gladkikh I., Chausova V., Monastyrnaya M., Anastyuk S., Chernikov O., Yurchenko E., Aminin D., Isaeva M., Leychenko E., Kozlovskaya E. Peptide fingerprinting of the sea anemone Heteractis magnifica mucus revealed neurotoxins, Kunitz-type proteinase inhibitors and a new β-defensin α-amylase inhibitor // Journal of Proteomics. 2018. Vol. 173. P. 12–21. https://doi: 10.1016/j.jprot.2017.11.019.
- 54. Sintsova O., Gladkikh I., Kalinovskii A., Zelepuga E., Monastyrnaya M., Kim N., Shevchenko ., Peigneur S., Tytgat J., Kozlovskaya E., Leychenko E. Magnificamide, a a-defensin-like peptide from the mucus of the sea anemone Heteractis magnifica, is a strong inhibitor of mammalian a-amylases // Mar. Drugs. 2019. Vol. 17. P. 542. https://doi: 10.3390/md17100542.
- 55. Tysoe C., Williams L. K., Keyzers R., Nguyen N. T., Tarling C., Wicki J., Goddard-Borger E.D., Aguda A. H., Perry S., Foster L. J., Andersen R. J., Brayer G. D., Wither S. G. Potent human α-amylase inhibition by the β-defensin-like protein Helianthamide // ACS Cent. Sci. 2016. Vol. 2, N3. P. 154–161. https://doi: 10.1021/acscentsci.5b00399.
- 56. Kalina R., Gladkikh I., Dmitrenok P., Chernikov O., Koshelev S., Kvetkina A., Kozlov S., Kozlovskaya E., Monastyrnaya M. New APETx-like peptides from sea anemone Heteractis crispa modulate ASIC1a channels // Peptides. 2018. Vol. 104. P. 41–49. https://doi.org/ 10.1016/j.peptides.2018.04.013.
- 57. Diochot S., Baron A., Rash L. D., Deval E., Escoubas P., Scarzello S., Salinas M., Lazdunski M. A new sea anemone peptide, APETx2, inhibits ASIC3, a major acid-sensitive channel in sensoryneurons // EMBO J. 2004. Vol. 23. P. 1516–1525. https://doi: 10.1038/sj.emboj.7600177.
- 58. Osmakov D. I., Andreev Y. A., Kozlov S. A. Acid-sensing ion channels and their modulators // Biochemistry. 2014. Vol. 79. P. 1528–1545. https://doi: 10.1134/S0006297914130069.
- 59. Kalina R. S., Koshelev S. G., Zelepuga E. A., Kim N. Y., Kozlov S. A., Kozlovskaya E. P., Monastyrnaya M. M., Gladkikh I. N. APETx-like peptides from the sea anemone Heteractis crispa, diverse in their effect on ASIC1a and ASIC3 ion channels // Toxins. 2020. Vol. 12, N4. 266 [1–20]. https://doi.org/ 10.3390/toxins12040266.