نوع مقاله : مقاله پژوهشی
نویسنده
گروه زیست شناسی، دانشگاه پیام نور، تهران، ایران
10.30473/eab.2025.74787.1996
چکیده
تب خونریزی‌دهندۀ کریمه–کنگو (CCHF) یک بیماری ویروسی زئونوز با مرگ‌ومیر بالاست که تاکنون درمان اختصاصی مؤثری برای آن معرفی نشده است. ویروس عامل بیماری، از جنس Nairovirus و خانواده Orthonairoviridae بوده و قطعه L ژنوم آن پلی‌پروتئینی را رمزگذاری می‌کند که حاوی آنزیم RNA-dependent RNA polymerase (RdRp) و دامنه پروتئازی OTU در بخش N-terminal است. دامنه OTU با فعالیت دی‌یوبی‌کوئیتینازی (DUB)، در سرکوب ایمنی میزبان نقش دارد و به‌دلیل توالی نسبتاً محافظت‌شده‌اش، هدفی مناسب برای طراحی داروهای ضدویروسی به‌شمار می‌رود. این پژوهش با هدف بررسی اثر مهاری ترکیب طبیعی Phellopterin (Phe) از گیاه Heracleum persicum بر دامنه OTU انجام شد؛ ترکیبی با ساختار فوروکومارینی مشابه مهارکننده‌های شناخته‌شده و برگزیده از میان ۵۰ لیگاند بر پایه انرژی اتصال و ویژگی‌های .ADMET ساختار بلورینOTU (PDB ID: 3PRP) پس از آماده‌سازی، با استفاده از نرم‌افزار AutoDock 4.0 مورد داکینگ قرار گرفت و کمپلکس حاصل طی شبیه‌سازی دینامیک مولکولی 150 نانوثانیه‌ای با روش‌های GROMACS بررسی شد. Phellopterin با انرژی اتصال مناسب (ΔG=-8.1 kcal/mol) به ناحیه ورودی جایگاه فعال متصل شده و تعاملات پایداری با باقی‌مانده‌هایی نظیر Ala79–Leu86 برقرار کرد، که این اتصال با تثبیت ساختار و انسداد نسبی مسیر فعال، می‌تواند موجب مهار غیررقابتی عملکرد آنزیم گردد. تحلیل‌های RMSD، RMSF، Rg، پیوندهای هیدروژنی و PCA، پایداری ساختاری کمپلکس را تأیید کردند. بررسی ADMET نیز پروفایل فارماکوکینتیکی، جذب خوراکی، نفوذپذیری سلولی و ایمنی مناسبی برای ترکیب نشان داد. بر این اساس، Phellopterin می‌تواند به‌عنوان مهارکننده بالقوه OTU ویروس CCHFV مطرح شود و زمینه‌ساز طراحی داروهای ضدویروسی طبیعی و مؤثر باشد؛ اگرچه تأیید این نتایج مستلزم مطالعات تجربی in vitro و in vivo است.
کلیدواژه‌ها
- ویروس تب خونریزی‌دهنده کریمه-کنگو
- Phellopterin
- RNA پلیمراز وابسته به RNA
- شبیه‌سازی داکینگ مولکولی
- فوروکومارینها
موضوعات
Aligholipour Farzani, T., Földes, K., Ergünay, K., Gurdal, H., Bastug, A., & Ozkul, A. (2019). Immunological analysis of a CCHFV mRNA vaccine candidate in mouse models. Vaccines, 7(3), 115.
Appannanavar, S. B., & Mishra, B. (2011). An update on Crimean Congo hemorrhagic fever. Journal of global infectious diseases, 3(3), 285-292.
Arab-Bafrani, Z., Jabbari, A., Mostakhdem Hashemi, M., Arabzadeh, A. M., Gilanipour, A., & Mousavi, E. (2019). Identification of the crucial parameters regarding the efficacy of ribavirin therapy in Crimean–Congo haemorrhagic fever (CCHF) patients: a systematic review and meta-analysis. Journal of Antimicrobial Chemotherapy, 74(12), 3432-3439.
Azari, M., Bahreini, F., Uversky, V. N., & Rezaei, N. (2023). Current therapeutic approaches and promising perspectives of using bioengineered peptides in fighting chemoresistance in triple-negative breast cancer. Biochemical Pharmacology, 210, 115459.
Capodagli, G. C., McKercher, M. A., Baker, E. A., Masters, E. M., Brunzelle, J. S., & Pegan, S. D. (2011). Structural analysis of a viral ovarian tumor domain protease from the Crimean-Congo hemorrhagic fever virus in complex with covalently bonded ubiquitin. Journal of virology, 85(7), 3621-3630.
Dai, S., Deng, F., Wang, H., & Ning, Y. (2021). Crimean-Congo hemorrhagic fever virus: current advances and future prospects of antiviral strategies. Viruses, 13(7), 1195.
Davey, M. G., Davies, M., Lowery, A. J., Miller, N., & Kerin, M.J. (2021). The role of microRNA as clinical biomarkers for breast cancer surgery and treatment. International Journal of Molecular Sciences, 22(15), 8290.
David, A. V. A., Arulmoli, R., & Parasuraman, S. (2016). Overviews of biological importance of quercetin: A bioactive flavonoid. Pharmacognosy reviews, 10(20), 84.
Dehnoee, A., Kalbasi, R. J., Tavakoli, S., Zangeneh, M. M., Zangeneh, A., & Delnavazi, M.-R. (2023). Anticancer potential of furanocoumarins and flavonoids of Heracleum persicum fruit.
Diakou, I., Papakonstantinou, E., Papageorgiou, L., Pierouli, K., Dragoumani, K., Spandidos, D. A., ... & Vlachakis, D. (2022). Novel computational pipelines in antiviral structure‑based drug design. Biomedical Reports, 17(6), 97.
Dokuzoguz, B., Celikbas, A. K., Gök, Ş. E., Baykam, N., Eroglu, M. N., & Ergönül, Ö. (2013). Severity scoring index for Crimean-Congo hemorrhagic fever and the impact of ribavirin and corticosteroids on fatality. Clinical infectious diseases, 57(9), 1270-1274.
Dowall, S., Buttigieg, K., Findlay-Wilson, S., Rayner, E., Pearson, G., Miloszewska, A., ... & Hewson, R. (2016). A Crimean-Congo hemorrhagic fever (CCHF) viral vaccine expressing nucleoprotein is immunogenic but fails to confer protection against lethal disease. Human vaccines & immunotherapeutics, 12(2), 519-527.
Dzimianski, J. V., Scholte, F. E., Williams, I. L., Langley, C., Freitas, B. T., Spengler, J. R., ... & Pegan, S. D. (2019). Determining the molecular drivers of species-specific interferon-stimulated gene product 15 interactions with nairovirus ovarian tumor domain proteases. PLoS One, 14(12), e0226415.
Farahmand, S., SamadiAfshar, S., Khalili, M., & Hosseini, R. H. (2025). Therapeutic implications of Epirubicin-induced miRNA-22 and miRNA-331 upregulation on cell viability and metastatic potential in triple-negative breast cancer. Human Gene, 44, 201396.
Frank, M. G., Weaver, G., & Raabe, V. (2024). Crimean Congo Hemorrhagic Fever Virus for Clinicians—Virology, Pathogenesis, and Pathology. Emerging Infectious Diseases, 30(5), 847.
Fu, Y., Yang, Q., Yang, H., & Zhang, X. (2023). New progress in the role of microRNAs in the diagnosis and prognosis of triple negative breast cancer. Frontiers in Molecular Biosciences, 10, 1162463.
Gerlach, P., Malet, H., Cusack, S., & Reguera, J. (2015). Structural insights into bunyavirus replication and its regulation by the vRNA promoter. Cell, 161(6), 1267-1279.
Hatcher, H., Planalp, R., Cho, J., Torti, F. M., & Torti, S. V. (2008). Curcumin: from ancient medicine to current clinical trials. Cellular and molecular life sciences, 65, 1631-1652.
Hawman, D. W., Haddock, E., Meade-White, K., Williamson, B., Hanley, P. W., Rosenke, K., … & Feldmann, H. (2018). Favipiravir (T-705) but not ribavirin is effective against two distinct strains of Crimean-Congo hemorrhagic fever virus in mice. Antiviral research, 157, 18-26.
Hawman, D. W., Meade-White, K., Leventhal, S., Feldmann, F., Okumura, A., Smith, B., … & Feldmann, H. (2021). Immunocompetent mouse model for Crimean-Congo hemorrhagic fever virus. Elife, 10, e63906.
Hawman, D. W., & Feldmann, H. (2023). Crimean–Congo haemorrhagic fever virus. Nature Reviews Microbiology, 21(7), 463-477
Kaushal, N., & Baranwal, M. (2023). Mutational analysis of catalytic site domain of CCHFV L RNA segment. Journal of Molecular Modeling, 29(4), 88.
Khandan Alamdari, S., Farahmand, S., Haji Hosseini, R., & Bakhshi Khaniki, G. (2023). Computational design of E6 protein inhibitors for the treatment of HPV16 disease. Experimental animal Biology, 12(2), 1-14.
Kocabaş, F., & Ergin, E. K. (2016). Identification of small molecule binding pocket for inhibition of Crimean? Congo hemorrhagic fever virus OTU protease. Turkish Journal of Biology, 40(1), 239-249.
Li, X., Wang, Y., Jiang, M., Yin, F., Zhang, H., Yuan, L., ... & Zhang, Z. (2024). Exploring the binding mechanism of a small molecular Hsp70-Bim PPI inhibitor through molecular dynamic simulation. Journal of Molecular Modeling, 30(3), 71.
Li, M. (2024). Innate immune response against vector-borne bunyavirus infection and viral countermeasures. Frontiers in Cellular and Infection Microbiology, 14, 1365221.
Mirza, M. U., Vanmeert, M., Froeyen, M., Ali, A., Rafique, S., & Idrees, M. (2019). In silico structural elucidation of RNA-dependent RNA polymerase towards the identification of potential Crimean-Congo Hemorrhagic Fever Virus inhibitors. Scientific reports, 9(1), 6809.
Moradi, S., Nowroozi, A., Nezhad, M. A., Jalali, P., Khosravi, R., & Shahlaei, M. (2024). A review on description dynamics and conformational changes of proteins using combination of principal component analysis and molecular dynamics simulation. Computers in Biology and Medicine, 183, 109245.
Moradi, G., Piroozi, B., Alinia, C., Safari, H., Nabavi, M., Zeinali, M., ... & Gouya, M. M. (2019). Incidence, mortality, and burden of crimean congo hemorrhagic fever and its geographical distribution in Iran during 2009-2015. Iranian Journal of Public Health, 48(Supple 1), 44-52.
Mustali, J., Yasuda, I., Hirano, Y., Yasuoka, K., Gautieri, A., & Arai, N. (2023). Unsupervised deep learning for molecular dynamics simulations: a novel analysis of protein–ligand interactions in SARS-CoV-2 M pro. RSC advances, 13(48), 34249-34261.
Pattnaik, A., Palermo, N., Sahoo, B. R., Yuan, Z., Hu, D., Annamalai, A. S., … & Destache, C. J. (2018). Discovery of a non-nucleoside RNA polymerase inhibitor for blocking Zika virus replication through in silico screening. Antiviral research, 151, 78-86.
Sakhawat, A., Khan, M. U., Rehman, R., Khan, S., Shan, M. A., Batool, A., … & Ali, Q. (2023). Natural compound targeting BDNF V66M variant: insights from in silico docking and molecular analysis. Amb Express, 13(1), 134.
Salaria, P., Akshinthala, P., & Kapavarapu, R. (2023). Identification of novel C-15 fluoro isosteviol derivatives for GABA-AT inhibition by in silico investigations. Journal of Molecular Modeling, 29(3), 76.
SamadiAfshar, S., NikAkhtar, A., SamadiAfshar, S., & Farahmand, S. (2024). Antibacterial Property of Silver Nanoparticles Green Synthesized from Stachys schtschegleevii Plant Extract on Urinary Tract Infection Bacteria. Current Microbiology, 81(5), 135.
Scholte, F. E., Zivcec, M., Dzimianski, J. V., Deaton, M. K., Spengler, J. R., Welch, S. R., … & Bergeron, É. (2017). Crimean-Congo hemorrhagic fever virus suppresses innate immune responses via a ubiquitin and ISG15 specific protease. Cell reports, 20(10), 2396-2407.
Scholte, F. E., Hua, B. L., Spengler, J. R., Dzimianski, J. V., Coleman-McCray, J. D., Welch, S. R., ... & Bergeron, É. (2019). Stable occupancy of the Crimean-Congo hemorrhagic fever virus-encoded deubiquitinase blocks viral infection. American Society for Microbiology (MBio), 10(4), 10-1128.
Shaito, A., Posadino, A. M., Younes, N., Hasan, H., Halabi, S., Alhababi, D., ... & Pintus, G. (2020). Potential adverse effects of resveratrol: A literature review. International journal of molecular sciences, 21(6), 2084.
Shojapour, M., & Farahmand, S. (2022). Point mutation consideration in CcO protein of the electron transfer chain by MD simulation. Journal of Molecular Graphics and Modelling, 117, 108309.
Shojapour, M., Farahmand, S., Fatemi, F., & Shasaltaneh, M. D. (2022). Evaluation of Cyc1 protein stability in Acidithiobacillus ferrooxidans bacterium after E121D mutation by molecular dynamics simulation to improve electron transfer. Journal of Microbiology, 60(5), 526-532.
Shojapour, M., Fatemi, F., Farahmand, S., & Shasaltaneh, M. D. (2021). Investigation of Cyc1 protein structure stability after H53I mutation using computational approaches to improve redox potential. Journal of Molecular Graphics and Modelling, 105, 107864.
Smee, D. F., Jung, K.-H., Westover, J., & Gowen, B. B. (2018). 2′-Fluoro-2′-deoxycytidine is a broad-spectrum inhibitor of bunyaviruses in vitro and in phleboviral disease mouse models. Antiviral research, 160, 48-54.
Tang, Q., Ouyang, H., He, D., Yu, C., & Tang, G. (2019). MicroRNA-based potential diagnostic, prognostic and therapeutic applications in triple-negative breast cancer. Artificial cells, nanomedicine, and biotechnology, 47(1), 2800-2809.
Verma, S. K. (2011). Molecular docking studies towards exploring active sites for antiviral compound against RdRP protein of Crimean-Congo hemorrhagic fever virus. BIOMIRROR, 2(12), 1-6.
Zivcec, M., Scholte, F. E., Spiropoulou, C. F., Spengler, J. R., & Bergeron, É. (2016). Molecular insights into Crimean-Congo hemorrhagic fever virus. Viruses, 8(4), 106.
)