Modification of hyaluronidase microenvironment: innovatory approaches for development of biocatalytic medical preparations

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Abstract

The computational study of 3D-model hyaluronidase interaction with shortchain glycosaminoglycan ligands had performed demonstrating the diversity and significance of their reaction on enzyme structure. The purpose of this review was evolution of limiting enzyme functioning interactions (impact on stability, biocatalyst activity) with grounding of recommendations for experimental modification of hyaluronidase for obtaining of its derivative of medicine destination (according the results of theoretical researches). The analysis was performed on databases of PubMed, Web of Science, MedLine, E-library in frames last 15 years. The binding of chondroitin trimers (on centers cn6, cn3, cn1) to hyaluronidase molecular surface increased the enzyme stability, binding of chondroitin sulfate trimers (on centers cs2, cs4, cs7, cs8 or cs1, cs2, cs4, cs7, cs8) decreased the inhibition of enzyme by tetramer heparin. It should be noted the importance of ligand binding for regulation of enzyme functioning and existence of multiform and multicomponent microenvironment of enzyme. The sequence of preferable coupling of ligands with hyaluronidase is elicited in our study and with its help was evaluate reality of experimental selective modification of enzyme (possibly noncovalent or covalently, for instance, with chondroitin sulfate trimers on centers cs7, cs1, cs5) for experimental obtaining of stabilized enzyme forms. The perspective approaches for this aim may be the noncovalent reaction on hyaluronidase by chondroitin or chondroitin sulfate trimers as well covalent modification of biocatalyst by chondroitin sulfate trimers.

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Alexander V. Maksimenko

Academician E.I. Chazov National Medical Research Center of Cardiology, Ministry of Healthcare of Russia

Author for correspondence.
Email: alex.v.maks@mail.ru
ORCID iD: 0000-0002-7431-231X

Leading Researcher, BIOENGINEERING TECHNOLOGIES and Scientific Researches Support Department of academician V.N. Smirnov Institute of experimental cardiology, Academician E.I. Chazov National Medical Research Center of Cardiology, Ministry of Healthcare of Russia

Russian Federation, Moscow, Academician E.I. Chazov St., 15А, 121552

References

  1. Максименко А.В., Сахарова Ю.С., Бибилашвили Р.Ш. Влияние гликозаминогликановых производных на функционирование гиалуронидазы. Экспериментальное исследование воздействия на нативный и модифицированный фермент. Кардиологический вестник. 2021; XVI (3): 15–22. https://doi.org/10.17116/Cardiobulletin20211603115. [Maksimenko A.V., Sakharova Yu.S., Beabealashvili R.S. Influence of glycosaminoglycan derivative on hyaluronidase function. Experimental study of effect on native and modified enzyme. Russian Cardiology Bulletin. 2021; XVI (3): 15–22 (in Russian)].
  2. Турашев А.Д., Тищенко Е.Г., Максименко А.В. Гликирование нативной и модифицированной хондроитинсульфатом гиалуронидазы моносахаридами. Молекулярная медицина. 2009; 3: 51–6. [Turashev A.D., Tischenko E.G., Maksimenko A.V. Glycation of native and modified by chondroitin sulfate hyaluronidase with monosaccharides. Molekulyarnaya meditsina. 2009; 3: 51–6 (in Russian)].
  3. Турашев А.Д., Тищенко Е.Г., Максименко А.В. Неферментативное гликозилирование нативной и модифицированной хондроитинсульфатом гиалуронидазы дисахаридами. Молекулярная медицина. 2009; 6: 50–5. [Turashev A.D., Tischenko E.G., Maksimenko A.V. Nonenzymatic glycosylation of native and modified by chondroitin sulfate hyaluronidase with disaccharides. Molekulyarnaya meditsina. 2009; 6: 50–5 (in Russian)].
  4. Di Cera E. Mechanisms of ligand binding. Biophysics Review. 2020; 1 (1): 011303. https://doi.org/10.1063/5.0020997
  5. Максименко А.В. Расчетный инструментарий, методы выполнения и развития молекулярного докинга ферментов медицинского назначения. Молекулярная медицина. 2020; 18 (2): 17–22. https://doi.org/1029296/24999490-2020-02-03 [Maksimenko A.V. Computational tools and methods for the implementation and elaboration of molecular docking for enzymes of the medical destination. Molekulyarnaya meditsina. 2020; 18 (2): 17–22 (in Russian)].
  6. Максименко А.В., Бибилашвили Р.Ш. Димеры и тримеры хондроитина в молекулярном докинге с бычьей тестикулярной гиалуронидазой. Биоорганическая химия. 2020; 46 (2): 151–7. https://doi.org/1031857/S0132342320020153 [Maksimenko A.V., Beabealashvili R.S. Dimers and trimers of chondroitin in molecular docking of bovine testicular hyaluronidase. Bioorganicheskaya himiya. 2020; 46 (2): 151–7 (in Russian).]
  7. Максименко А.В., Бибилашвили Р.Ш. Влияние гиалуронидазного микроокружения на соотношение структура-функция фермента и вычислительное исследование in silico молекулярного докинга гиалуронидазы с короткими фрагментами хондроитинсульфата и гепарина. Известия Академии наук. Серия химическая. 2018; 64 (4): 636–46. https://doi.org/10.1007/s11172-018-2117-4 [Maksimenko A.V., Beabeabilashvili R.Sh. The influence of hyaluronidase microenvironment on structure-enzyme function ratio and computational study in silico the molecular docking of hyaluronidase with short length fragments of chondroitin sulfate and heparin. Russian Chemical Bulletin. International Edition. 2018; 67 (4): 636–46 (in Russian)].
  8. Максименко А.В., Бибилашвили Р.Ш. Конформационные переходы на 3D-модели бычьей тестикулярной гиалуронидазы при молекулярном докинге с гликозаминогликановыми лигандами. Биоорганическая химия. 2018; 44 (2): 147–57. https://doi.org/10.1134/S1068162018020048 [Maksimenko A.V., Beabealashvili R.S. Conformational alterations of bovine testicular hyaluronidase 3D-model during molecular docking with glycosaminoglycan ligands. Bioorganicheskaya himiya. 2018; 44 (2): 147–57 (in Russian)].
  9. Maksimenko A.V. Theoretical research of interactions between glycosidases and glycosaminoglycan ligands with molecular docking and molecular dynamics methods. Cardiology and cardiovascular research. 2021; 16 (4): 220–30. https://doi.org/10.11648/j.ccr20200404.19
  10. Максименко А.В., Щечилина Ю.В., Тищенко Е.Г. Гликозаминогликановое микроокружение гиалуронидазы в регуляции ее эндогликозидазной активности. Биохимия. 2003; 68 (8): 1055–62. [Maksimenko A.V., Schechilina Y.V., Tischenko E.G. The glycosaminoglycan microenvironment of hyaluronidase for regulation of its endoglycosidase activity. Biochemistry (Moscow). 2003; 68 (8): 1055–62 (in Russian)].
  11. Maksimenko A.V., Sakharova Y.S., Beabealashvili R.S. Experimental and computational study of hyaluronidase interactions with glycosaminoglycans and their ligands. Current Molecular Medicine. 2022; 22 (8): 675–90. https://doi.org/10.2174/1566524021666211014161716
  12. Максименко А.В. Кардиологические биофармацевтики в концепции направленного транспорта лекарств: практические результаты и исследовательские перспективы. Acta Naturae. 2012; 4 (3): 76–86. https://ncbi.nlm.nih.gov/pmc/articles/PMC3491893 [Maksimenko A.V. Cardiological biopharmaceuticals in the conception of drug targeting delivery: practical results and research perspectives. Acta Naturae. 2012; 4 (3): 76–86 (in Russian)].
  13. Lokeshwar V.B., Mirza S., Jordan A. Targeting hyaluronic acid family for cancer chemoprevention and therapy. Advanced Cancer Research. 2014; 123: 35–65 https://doi.org/10.1016/B978-0-12-800092-2.00002-2
  14. Washington P.M., Lee C., Dwyer M.K.R., Konofagou E.E., Kernie S.G., Morrison III, B. Hyaluronidase reduced edema after experimental traumatic brain injury. J. of Cerebral Blood Flow and Metabolism. 2020; 40 (10): 2026–37. https://doi.org/10.1177/0271678X19882780
  15. Kiyokawa J., Kawamura Y., Ghouse S.M., Acar S., Barcin E., Martinez-Quintanilla J., Martuza R.L., Alemany R., Rabkin S.D., Shah K., Wakimoto H. Modification of extracellular matrix enhances adenovirus immunotherapy in glioblastoma. Clinical Cancer Research. 2021; 27 (3): 889–902. https://doi.org/10.1158/1078-0432.CCR-20-2400
  16. Feng C., Xiong Z., Wang C., Xiao W., Xiao H., Xie K., Chen K., Liang H., Zhang X., Yang H. Folic acid-modified exosome-PH20 enhances the efficiency of therapy via modulation of the tumor microenvironment and directly inhibits tumor cell metastasis. Bioactive Materials. 2021; 6: 963–74. https://doi.org/10.1016/j.bioactmat.2020.09.014
  17. Hingorani S.R., Harris W.P., Beck J.T., Berdov B., Wagner S.A., Pshevlotsky E.M., Njulandin SA, Gladkov O.A., Holkombe R.F., Korn R., Raghunand N., Dychter S., Jiang P., Shepard H.M., Devoe C.E. Phase Ib study of PEGylated recombinant human hyaluronidase and gemcitabine in patients with advanced pancreatic cancer. Clinical Cancer Research. 2016; 22 (12): 2848–54. https://10/1158/1078-0432.CCR-15-2010
  18. Maneval D.C., Caster C.L., Derunes C., Locke K.W., Muhsin M., Sauter S., Sekulovich R.E., Thompson C.B., LaDarre M.J. Pegvorhyaluronidase alfa: a PEGylated recombinant human hyaluronidase PH20 for the treatment of cancer that accumulate hyaluronan. In: Polymer-Protein Conjugates. Eds. Pasut G., Zalipsky S. Elsevier. 2020; 175–204. https://doi.org/10.1016/B978-0-444-64081-9/000009-7

Supplementary files

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2. Fig. 1. Binding of the CH dimers and trimers at 8 binding sites (designated as 1, 2, 3, etc.) on molecular surface of bovine testicular hyaluronidase (BTH). The hyaluronidase molecule in the figure is oriented parallel to the main inertia axis of the protein along the horizontal axis, while the substrate valley is oriented so that the main inertia axis of the 12-member substrate is perpendicular to the figure plane. The hyaluronidase molecule is depicted in ribbon form; alpha-helical regions are shown dark gray, beta-structures are gray, and the rest of the molecule, light gray. GAG ligands are depicted as small balls connected with cylinders; Na and Cl ions, as small balls, and water molecules, thin clear gray lines. Sites 1, 2, 3, and 7 are located in the figure plane (sites 1 and 7 are located in the middle, site 2 closer to the observer, and 3, further form the observer), sites 4, 5, and 8 are located on the distal side of the protein molecule, and site 6 occupies the substrate valley, its position being perpendicular to the figure plane

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3. Fig. 2. 3D model of BTH with electrostatically bound eight chondroitin sulfate trimers when theoretically stabilize the enzyme structure against inhibition with heparin tetramer (at site cs6) in the active center of the biocatalyst possibly with binding at cs2, cs4, cs7 and cs8 sites already

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4. Fig. 3. Form of the surface isoelectric potential of 3D model of BTH with electrostatically bound chondroitin sulfate trimers (at the level of 0.4 e/ao) when theoretically stabilize the enzyme structure against inhibition with heparin tetramer (at cs6) in the active center of the enzyme (а) possibly with binding at cs2, cs4, cs7 and cs8 sites already. View of the surface isoelectric potential (at the level of 0.4 e/ao) of free BTH molecules (б). Negative electrostatic potential values are colored dark gray, positive values light gray

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