Фармакологическая и генетическая модуляция белков теплового шока: современные подходы и перспективы терапии

Молекулярные шапероны, или белки теплового шока (HSP, heat shock proteins), представляют собой консервативный класс белков, отвечающих за правильную укладку полипептидов и предотвращение их неправильного сворачивания и агрегации, тем самым поддерживая клеточный протеостаз. Эти белки классифицируются по молекулярной массе на несколько семейств (включая HSP40, HSP60, HSP70, HSP90, HSP110 и малые HSP) и действуют в координации с ко-шаперонами в качестве центральных компонентов системы клеточного контроля качества белков. Шапероны участвуют во множестве процессов: сворачивание de novo синтезируемых белков, рефолдинг денатурированных или нестабильных белков, сборка белковых комплексов, растворение агрегатов и деградация дефектных полипептидов. Благодаря этим механизмам HSP защищают клетки от стресса (например, теплового удара) и поддерживают гомеостаз белков; активация шаперонного ответа регулируется тепловыми факторами транскрипции (HSF) при стрессовых воздействиях.
Дисфункция или дисбаланс активности шаперонов связаны с развитием ряда заболеваний: при нейродегенеративных заболеваниях накопление токсичных белковых агрегатов (таких как амилоид-бета и тау при болезни Альцгеймера) смягчается за счёт работы HSP, а при онкологических заболеваниях чрезмерная экспрессия HSP способствует выживанию и злокачественной прогрессии опухолевых клеток. Учитывая ключевую роль шаперонов, ведутся активные исследования по их таргетной модуляции. Фармакологические ингибиторы HSP90 уже проходят клинические испытания как противоопухолевые препараты, индукторы HSF1/шаперонов и генные стратегии рассматриваются для усиления протеостаза при протеинопатиях. Перспективными направлениями также являются вакцины на основе комплексов HSP–антигенов (использующие шапероны как адъюванты для стимуляции иммунного ответа) и протеостаз-ориентированные терапии, нацеленные на восстановление баланса белкового гомеостаза в клетке.

1. Sinnige T., Yu A., Morimoto R.I. Challenging Proteostasis: Role of the Chaperone Network to Control Aggregation-Prone Proteins in Human Disease. Adv Exp Med Biol. 2020;1243:53-68. https://doi.org/10.1007/978-3-030-40204-4_4

2. Hervás R., Oroz J. Mechanistic Insights into the Role of Molecular Chaperones in Protein Misfolding Diseases: From Molecular Recognition to Amyloid Disassembly. Int J Mol Sci. 2020;21(23):9186. Published 2020 Dec 2. https://doi.org/10.3390/ijms21239186

3. Gestwicki J.E., Shao H. Inhibitors and chemical probes for molecular chaperone networks. J Biol Chem. 2019;294(6):2151-2161. https://doi.org/10.1074/jbc.TM118.002813

4. Chakafana G., Makumire S., Makhoba X.H. Editorial: Molecular chaperones and human disease. Front Mol Biosci. 2022;9:1068238. https://doi.org/10.3389/fmolb.2022.1068238

5. Mitra R., Wu K., Lee C., Bardwell J.C.A. ATP-Independent Chaperones. Annu Rev Biophys. 2022;51:409-429. https://doi.org/10.1146/annurev-biophys-090121-082906

6. Gardner S., Darrow M.C., Lukoyanova N., et al. Structural basis of substrate progression through the bacterial chaperonin cycle. Proc Natl Acad Sci U S A. 2023;120(50):e2308933120. https://doi.org/10.1073/pnas.2308933120

7. Wentink A., Nussbaum-Krammer C., Bukau B. Modulation of Amyloid States by Molecular Chaperones. Cold Spring Harb Perspect Biol. 2019;11(7):a033969. https://doi.org/10.1101/cshperspect.a033969

8. Castelli M., Magni A., Bonollo G., et al. Molecular mechanisms of chaperone-directed protein folding: Insights from atomistic simulations. Protein Sci. 2023;33(3):e4880. https://doi.org/10.1002/pro.4880

9. Astl L., Stetz G., Verkhivker G.M. Dissecting Molecular Principles of the Hsp90 Chaperone Regulation by Allosteric Modulators Using a Hierarchical Simulation Approach and Network Modeling of Allosteric Interactions: Conformational Selection Dictates the Diversity of Protein Responses and Ligand-Specific Functional Mechanisms. J Chem Theory Comput. 2020;16(10):6656-6677. https://doi.org/10.1021/acs.jctc.0c00503

10. Musskopf M.K., de Mattos E.P., Bergink S., Kampinga H.H. Hsp40/DNAJ chaperones. eLS. 2018. https://doi.org/10.1002/9780470015902.a0027633

11. Abildgaard A.B., Gersing S.K., Larsen-Ledet S., et al. CoChaperones in Targeting and Delivery of Misfolded Proteins to the 26S Proteasome. Biomolecules. 2020;10(8):1141. https://doi.org/10.3390/biom10081141

12. Singh M.K., Shin Y., Han S., et al. Molecular Chaperonin HSP60: Current Understanding and Future Prospects. Int J Mol Sci. 2024;25(10):5483. https://doi.org/10.3390/ijms25105483

13. Arhar T., Shkedi A., Nadel C.M., Gestwicki J.E. The interactions of molecular chaperones with client proteins: why are they so weak?. J Biol Chem. 2021;297(5):101282. https://doi.org/10.1016/j.jbc.2021.101282

14. Biebl M.M., Lopez A., Rehn A., et al. Structural elements in the flexible tail of the co-chaperone p23 coordinate client binding and progression of the Hsp90 chaperone cycle. Nat Commun. 2021;12(1):828. https://doi.org/10.1038/s41467-021-21063-0

15. Takeuchi T. Non-cell Autonomous Maintenance of Proteostasis by Molecular Chaperones and Its Molecular Mechanism. Biol Pharm Bull. 2018;41(6):843-849. https://doi.org/10.1248/bpb.b18-00141

16. Hosaka Y., Araya J., Fujita Y., Kuwano K. Role of chaperonemediated autophagy in the pathophysiology including pulmonary disorders. Inflammation and regeneration. 2021;41(1):29. https://doi.org/10.1186/s41232-021-00180-9

17. Pandey M., Nabi J., Tabassum N., et al. Molecular Chaperones in Neurodegeneration. Quality Control of Cellular Protein in Neurodegenerative Disorders. 2020. https://doi.org/10.4018/978-1-7998-1317-0.ch014

18. Rastogi S., Joshi A., Sato N., et al. An update on the status of HSP90 inhibitors in cancer clinical trials. Cell stress & chaperones. 2024;29(4):519–539. https://doi.org/10.1016/j.cstres.2024.05.005

19. Condelli V., Crispo F., Pietrafesa M., et al. HSP90 Molecular Chaperones, Metabolic Rewiring, and Epigenetics: Impact on Tumor Progression and Perspective for Anticancer Therapy. Cells. 2019;8(6):532. https://doi.org/10.3390/cells8060532

20. Jafari A., Rezaei-Tavirani M., Farhadihosseinabadi B., et al. HSP90 and Co-chaperones: Impact on Tumor Progression and Prospects for Molecular-Targeted Cancer Therapy. Cancer Invest. 2020;38(5):310-328. https://doi.org/10.1080/07357907.2020.1752227

21. Bylicky M.A., Shankavaram U., Aryankalayil M.J., et al. MultiomicBased Molecular Landscape of FaDu Xenograft Tumors in Mice after a Combinatorial Treatment with Radiation and an HSP90 Inhibitor Identifies Adaptation-Induced Targets of Resistance and Therapeutic Intervention. Mol Cancer Ther. 2024;23(4):577-588. https://doi.org/10.1158/1535-7163.MCT-23-0796

22. Du S., Liu Y., Yuan Y., et al. Advances in the study of HSP70 inhibitors to enhance the sensitivity of tumor cells to radiotherapy. Frontiers in cell and developmental biology. 2022;10:942828. https://doi.org/10.3389/fcell.2022.942828

23. Yang J., Gong W., Wu S., et al. PES inhibits human-inducible Hsp70 by covalent targeting of cysteine residues in the substrate-binding domain. The Journal of biological chemistry. 2021;296:100210. https://doi.org/10.1074/jbc.RA120.015440

24. Wilson J., Gestwicki J., Korkaya H., et al. Abstract 4606: Heat shock proteins in immunosuppressive tumor microenvironment. Cancer. 2023;83(7):4606. https://doi.org/10.1158/1538-7445.am2023-4606

25. Zhao K., Zhou G., Liu Y., et al. HSP70 Family in Cancer: Signaling Mechanisms and Therapeutic Advances. Biomolecules. 2023;13(4):601. https://doi.org/10.3390/biom13040601

26. Martín-Peña A., Rincón-Limas D.E., Fernandez-Fúnez P. Engineered Hsp70 chaperones prevent Aβ42-induced memory impairments in a Drosophila model of Alzheimer’s disease. Sci Rep. 2018;8(1):9915. https://doi.org/10.1038/s41598-018-28341-w

27. Hu S., Tan J., Qin L., et al. Molecular chaperones and Parkinson’s disease. Neurobiol Dis. 2021;160:105527. https://doi.org/10.1016/j.nbd.2021.105527

28. Doke R., Kawade P., Nagrik S., et al. Navigating the cellular pathways: Chaperone-mediated autophagy as a targeted approach for management of parkinson’s disease. Journal of Pharmaceutical and Biological Sciences. 2023;11(1):26-29. https://doi.org/10.18231/j.jpbs.2023.005

29. Konstantinova E.V., Chipigina N.S., Shurdumova M.H., et al. Heat Shock Protein 70 kDa as a Target for Diagnostics and Therapy of Cardiovascular and Cerebrovascular Diseases. Curr Pharm Des. 2019;25(6):710-714. https://doi.org/10.2174/1381612825666190329123924

30. Liu W., Zhu S.O., Guo Y.L., et al. BL-918, a small-molecule activator of ULK1, induces cytoprotective autophagy for amyotrophic lateral sclerosis therapy. Acta pharmacologica Sinica. 2023;44(3):524–537. https://doi.org/10.1038/s41401-022-00972-w

31. Benatar M., Hansen T., Rom D., et al. ORARIALS-01 trial team. Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. The Lancet. Neurology. 2024;23(7):687–699. https://doi.org/10.1016/S1474-4422(24)00134-0

32. Mengel, E., Patterson, M., Da Riol, R., et al. Efficacy and safety of arimoclomol in Niemann-Pick disease type C: Results from a doubleblind, randomised, placebo-controlled, multinational phase 2/3 trial of a novel treatment. Journal of Inherited Metabolic Disease. 2021;44:1463 – 1480. https://doi.org/10.1002/jimd.12428

33. Zhang D., Zhang W., Ming C., et al. P-tau217 correlates with neurodegeneration in Alzheimer’s disease, and targeting p-tau217 with immunotherapy ameliorates murine tauopathy. Neuron. 2024;112(10):1676–1693.e12. https://doi.org/10.1016/j.neuron.2024.02.017

34. Cai M., Wu P., Ni W., et al. mTORC1 hyperactivation and resultant suppression of macroautophagy contribute to the induction of cardiomyocyte necroptosis by catecholamine surges. Physiological reports. 2024;12(5):e15966. https://doi.org/10.14814/phy2.15966

35. Carosi J. M., Sargeant T. J. Rapamycin and Alzheimer disease: a hypothesis for the effective use of rapamycin for treatment of neurodegenerative disease. Autophagy. 2024;19(8):2386–2390. https://doi.org/10.1080/15548627.2023.2175569

36. Mavroeidi P., Arvanitaki F., Vetsi M., et al. Autophagy mediates the clearance of oligodendroglial SNCA/alpha-synuclein and TPPP/p25A in multiple system atrophy models. Autophagy. 2022;18(9):2104–2133. https://doi.org/10.1080/15548627.2021.2016256

37. Padula L., Fisher E., Rivas K., et al. Secreted heat shock protein gp96-Ig and OX40L-Fc combination vaccine enhances SARS-CoV-2 Spike (S) protein-specific B and T cell immune responses. Vaccine: X. 2022;12:100202. https://doi.org/10.1016/j.jvacx.2022.100202

38. Sedlacek A., Watkins S., Nayak D., et al. CD91 and its ligand heat shock proteins regulate dendritic cell functions during immunosurveillance of emerging tumors. The Journal of Immunology. 2024;212(1):1463_4611. https://doi.org/10.4049/jimmunol.212.supp.1463.4611

39. Shevtsov M., Multhoff G. Heat Shock Protein-Peptide and HSPBased Immunotherapies for the Treatment of Cancer. Frontiers in immunology. 2016;7:171. https://doi.org/10.3389/fimmu.2016.00171

40. Belli F., Testori A., Rivoltini L., et al. Vaccination of metastatic melanoma patients with autologous tumor-derived heat shock protein gp96-peptide complexes: clinical and immunologic findings. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2002;20(20):4169–4180. https://doi.org/10.1200/JCO.2002.09.134

41. Wood C., Srivastava P., Bukowski R., et al. An adjuvant autologous therapeutic vaccine (HSPPC-96; vitespen) versus observation alone for patients at high risk of recurrence after nephrectomy for renal cell carcinoma: a multicentre, open-label, randomised phase III trial. Lancet (London, England). 2008;372(9633);145–154. https://doi.org/10.1016/S0140-6736(08)60697-2

42. Gong J., Zhang Y., Durfee J., et al. A heat shock protein 70-based vaccine with enhanced immunogenicity for clinical use. Journal of immunology . 2010;184(1):488–496. https://doi.org/10.4049/jimmunol.0902255

43. Asl N., Hajifathali A., Ghaemi F., et al. Hsp70, in Combination with IL-15 and PD-1 Blocker, Interferes with The Induction of Cytotoxic NK Cells in Relapsed Acute Myeloid Leukemia Patients. Cell Journal (Yakhteh). 2023;25:92 – 101. https://doi.org/10.22074/CELLJ.2023.561054.1123

44. Padula L., Fisher E., Wijayalath W., et al. Induction of antigen specific intrahepatic CD8+ T cell responses by a secreted heat shock protein based gp96-Ig-PfCA malaria vaccine. Frontiers in immunology. 2023;14:1130054. https://doi.org/10.3389/fimmu.2023.1130054

45. Hu Z., Yang J., Zhang S., et al. AAV mediated carboxyl terminus of Hsp70 interacting protein overexpression mitigates the cognitive and pathological phenotypes of APP/PS1 mice. Neural Regen Res. 2025;20(1):253-264. https://doi.org/10.4103/NRR.NRR-D-23-01277

46. Чичёва, М., Вихарева, Е., Вихарев, Ю., и др. Белок теплового шока hsp70 модулирует нейродегенеративный процесс в трансгенной модели протеинопатии. Russian Scientist. 2018;2:3-12.

47. Ahmed M., Greensmith L., Spicer C., et al. Amplifying the Heat Shock Response Ameliorates ALS and FTD Pathology in Mouse and Human Models. Molecular Neurobiology. 2023;60:6896 – 6915. https://doi.org/10.1007/s12035-023-03509-2