Problems of VirologyProblems of VirologyВопросы вирусологии0507-40882411-2097Central Research Institute for Epidemiology1688810.36233/0507-4088-405pwdezcREVIEWSОБЗОРЫReview ArticleNucleoside analogues in etiotropic therapy of hantavirus feversНуклеозидные аналоги в этиотропной терапии хантавирусных лихорадокhttps://orcid.org/0000-0003-1143-9732VetrovaAnna N.ВетроваАнна Николаевна
Russian Federation

junior researcher, Laboratory of Hemorrhagic Fever

младший научный сотрудник лаборатории геморрагических лихорадок

vetrova_an@chumakovs.suhttps://orcid.org/0000-0001-9934-699XKurashovaSvetlana S.КурашоваСветлана Сергеевна
Russian Federation

PhD (Med.), leading researcher, Laboratory of Hemorrhagic Fever

канд. мед. наук, ведущий научный сотрудник лаборатории геморрагических лихорадок

kurashova_ss@chumakovs.suhttps://orcid.org/0000-0003-3642-6444EgorovaMaria S.ЕгороваМария Сергеевна

PhD (Biol.), senior researcher, Laboratory of Hemorrhagic Fever

канд. биол. наук, старший научный сотрудник лаборатории геморрагических лихорадок

kurashova_ss@chumakovs.suhttps://orcid.org/0000-0002-6656-1682DzagurovaTamara K.ДзагуроваТамара Казбековна
Russian Federation

Dr Sci. (Med.), Head of the laboratory

д-р мед. наук, заведующая лабораторией геморрагических лихорадок

centrglps@yandex.ruChumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products of Russian Academy of Sciences (Institute of Poliomyelitis)ФГАНУ «Федеральный научный центр исследований и разработки иммунобиологических препаратов им. М.П. Чумакова РАН» (Институт полиомиелита)1709202671431131905052026Copyright ©; 2026, Vetrova A.N., Kurashova S.S., Egorova M.S., Dzagurova T.K.Copyright ©; 2026, Ветрова А.Н., Курашова С.С., Егорова М.С., Дзагурова Т.К.2026Vetrova A.N., Kurashova S.S., Egorova M.S., Dzagurova T.K.Ветрова А.Н., Курашова С.С., Егорова М.С., Дзагурова Т.К.https://creativecommons.org/licenses/by/4.0https://virusjour.crie.ru/jour/article/view/16888

Hantavirus fevers (HF) are caused by pathogenic orthohantaviruses and are classified into two clinical forms: hemorrhagic fever with renal syndrome (HFRS), reported in Eurasia, and hantavirus pulmonary syndrome (HPS), reported in the Americas.

HF are characterised by an acute course with predominant involvement of internal organs: HFRS is mainly associated with kidney damage, while HPS is characterised by severe lung injury. Both diseases may also affect the central nervous and endocrine systems. In addition, hantavirus fevers are marked by severe complications during the acute phase and a prolonged recovery period.

Currently, there is neither a WHO-approved vaccine nor any effective etiotropic anti-hantavirus therapy. The development of antiviral treatment strategies focuses on preventing orthohantavirus entry into cells or suppressing their intracellular replication. One of the main directions in the search for effective anti-hantavirus therapy is the low-molecular-weight compounds development and testing, many of which have demonstrated pronounced antiviral activity against orthohantaviruses through direct or indirect effects on viral RNA polymerase function.

The review shows that new antiviral nucleoside compounds development and study has promising potential, as well as their combined use for effective etiotropic, pathogenetic and symptomatic treatment of hantavirus fevers.

Хантавирусные лихорадки (ХЛ) связаны с патогенными ортохантавирусами и подразделяются на две клинические формы: геморрагическую лихорадку с почечным синдромом (ГЛПС), регистрируемую в Евразии, и хантавирусный пульмонарный синдром (ХПС), регистрируемый на Американском континенте.

ХЛ характеризуются острым течением с преимущественным поражением почек при ГЛПС и тяжелым поражением легких при ХПС. Оба заболевания также могут сопровождаться вовлечением центральной нервной и гормональной систем. Помимо этого, ХЛ характеризуются наличием тяжелых осложнений в остром периоде и длительным сроком реабилитации.

В настоящее время не существует ни одобренной ВОЗ вакцины, ни эффективной этиотропной противохантавирусной терапии. В качестве противовирусной терапии разрабатываются препараты, направленные на предупреждение проникновения ортохантавирусов в клетки или подавление их внутриклеточной репликации. Одним из основных направлений поиска эффективной противохантавирусной терапии является разработка и тестирование низкомолекулярных соединений, многие из которых показали выраженную противовирусную активность в отношении ортохантавирусов за счет прямого или косвенного влияния на функцию вирусной РНК-полимеразы.

Цель обзора – анализ данных литературы о нуклеозидных аналогах, рассматриваемых в качестве потенциальных препаратов для этиотропной терапии ХЛ.

Результаты обзора показывают перспективность разработки и исследования новых противовирусных нуклеозидных соединений, а также их комбинированного применения для эффективного этиотропного, патогенетического и симптоматического лечения ХЛ.

hemorrhagic fever with renal syndromeHFRSreviewhantavirus infectionsantiviral agentsantiviral compoundsribavirinfavipiravirETARzidovudineamantadineselenazofurinгеморрагическая лихорадка с почечным синдромомГЛПСобзорхантавирусные лихорадкипротивовирусные препаратыпротивовирусные соединениярибавиринфавипиравирETARзидовудинамантадинселеназофуринTkachenko E., Dzagurova T., Galieva G., Ivanis V., Kurashova S., Tkachenko P., et al. Clinical manifestations of hemorrhagic fever with renal syndrome, various nosologic forms and issues of hantavirus infections terminology. Viruses. 2025; 17(4): 578. https://doi.org/10.3390/v17040578 https://elibrary.ru/ozusudAfzal S., Ali L., Batool A., Afzal M., Kanwal N., Hassan M., et al. Hantavirus: an overview and advancements in therapeutic approaches for infection. Front. Microbiol. 2023; 14: 1233433. https://doi.org/10.3389/fmicb.2023.1233433 https://elibrary.ru/vexiulБернштейн А., Гавриловская И., Апекина Н., Дзагурова Т., Ткаченко Е. Особенности природной очаговости хантавирусных зоонозов. Эпидемиология и вакцинопрофилактика. 2010; 2: 5–13. Bernshtejn A., Gavrilovskaya I., Apekina N., Dzagurova T., Tkachenko E. Osobennosti prirodnoj ochagovosti hantavirusnyh zoonozov. Epidemiologiya i vakcinoprofilaktika. 2010; 2: 5–13. (in Russian)Szabó R. Antiviral therapy and prevention against hantavirus infections. Acta Virol. 2017; 61(1): 3–12. https://doi.org/10.4149/av_2017_01_3Kuhn J.H., Schmaljohn C.S. A brief history of bunyaviral family Hantaviridae. Diseases. 2023; 11(1): 38. https://doi.org/10.3390/diseases11010038 https://elibrary.ru/kohnjmWatson D., Sargianou M., Papa A., Chra P., Starakis I., Panos G. Epidemiology of Hantavirus infections in humans: A comprehensive, global overview. Crit. Rev. Microbiol. 2014; 40(3): 261–72. https://doi.org/10.3109/1040841x.2013.783555 https://elibrary.ru/sojnkzNoack D., Goeijenbier M., Reusken C., Koopmans M.P.G., Rockx B.H.G. Orthohantavirus pathogenesis and cell tropism. Front. Cell. Infect. Microbiol. 2020; 10: 399. https://doi.org/10.3389/fcimb.2020.00399 https://elibrary.ru/wgvrrwWernly J., Dietl C., Tabe C., Pett S.B., Crandall C., Milligan K., et al. Extracorporeal membrane oxygenation support improves survival of patients with Hantavirus cardiopulmonary syndrome refractory to medical treatment. Eur. J. Cardiothorac. Surg. 2011; 40(6): 1334–40. https://doi.org/10.1016/j.ejcts.2011.01.089Jonsson C., Figueiredo L., Vapalahti O. A global perspective on hantavirus ecology, epidemiology, and disease. Clin. Microbiol. Rev. 2010; 23(2): 412–41. https://doi.org/10.1128/CMR.00062-09 https://elibrary.ru/mydgxvRaftery M.J., Lalwani P., Lüttek N., Kobak L., Giese T., Ulrich R.G., et al. Replication in the mononuclear phagocyte system (MPS) as a determinant of hantavirus pathogenicity. Front. Cell. Infect. Microbiol. 2020; 10: 281. https://doi.org/10.3389/fcimb.2020.00281 https://elibrary.ru/sucwssBrocato R.L., Hooper J.W. Progress on the prevention and treatment of hantavirus disease. Viruses. 2019; 11(7): 610. https://doi.org/10.3390/v11070610 https://elibrary.ru/myzpxcDuffy S., Shackelton L.A., Holmes E.C. Rates of evolutionary change in viruses: patterns and determinants. Nat. Rev. Genet. 2008; 9(4): 267–76. https://doi.org/10.1038/nrg2323 https://elibrary.ru/yynevnSidwell R.W., Robins R.K., Hillyard I.W. Ribavirin: an antiviral agent. Pharmacol. Ther. 1979; 6(1): 123–46. https://doi.org/10.1016/0163-7258(79)90058-5 https://elibrary.ru/xvtanyTejada S., Martinez-Reviejo R., Karakoc H.N., Peña-López Y., Manuel O., Rello J. Ribavirin for treatment of subjects with respiratory syncytial virus-related infection: a systematic review and meta-analysis. Adv. Ther. 2022; 39(9): 4037–51. https://doi.org/10.1007/s12325-022-02256-5 https://elibrary.ru/cqixygZimmerman T.P., Deeprose R.D. Metabolism of 5-amino-1-beta-D-ribofuranosylimidazole-4-carboxamide and related five-membered heterocycles to 5’-triphosphates in human blood and L5178Y cells. Biochem. Pharmacol. 1978; 27(5): 709–16. https://doi.org/10.1016/0006-2952(78)90508-7Beaucourt S., Vignuzzi M. Ribavirin: a drug active against many viruses with multiple effects on virus replication and propagation. Molecular basis of ribavirin resistance. Curr. Opin. Virol. 2014; 8: 10–5. https://doi.org/10.1016/j.coviro.2014.04.011Severson W.E., Schmaljohn C.S., Javadian A., Jonsson C.B. Ribavirin causes error catastrophe during Hantaan virus replication. J. Virol. 2003; 77(1): 481–8. https://doi.org/10.1128/jvi.77.1.481-488.2003Tam R.C., Lau J.Y., Hong Z. Mechanisms of action of ribavirin in antiviral therapies. Antivir. Chem. Chemother. 2001; 12(5): 261–72. https://doi.org/10.1177/095632020101200501Graci J.D., Cameron C.E. Mechanisms of action of ribavirin against distinct viruses. Rev. Med. Virol. 2006; 16(1): 37–48. https://doi.org/10.1002/rmv.483Rusnak J.M., Byrne W.R., Chung K.N., Gibbs P.H., Kim T.T., Boudreau E.F., et al. Experience with intravenous ribavirin in the treatment of hemorrhagic fever with renal syndrome in Korea. Antiviral Res. 2009; 81(1): 68–76. https://doi.org/10.1016/j.antiviral.2008.09.007Shah N.R., Sunderland A., Grdzelishvili V.Z. Cell type mediated resistance of vesicular stomatitis virus and Sendai virus to ribavirin. PloS One. 2010; 5(6): e11265. https://doi.org/10.1371/journal.pone.0011265Kirsi J.J., North J.A., McKernan P.A., Murray B.K., Canonico P.G., Huggins J.W., et al. Broad-spectrum antiviral activity of 2-ß-D-ribofuranosylselenazole-4-carboxamide, a new antiviral agent. Antimicrob. Agents Chemother. 1983; 24(3): 353–61. https://doi.org/10.1128/AAC.24.3.353Huggins J.W. Prospects for treatment of viral hemorrhagic fevers with ribavirin, a broad-spectrum antiviral drug. Rev. Infect. Dis. 1989; 11(Suppl. 4): S750–61. https://doi.org/10.1093/clinids/11.supplement_4.s750Wei F., Li J.L., Ling J.X., Chen L.J., Li N., Liu Y.Y., et al. Establishment of SYBR green-based qPCR assay for rapid evaluation and quantification for anti-Hantaan virus compounds in vitro and in suckling mice. Virus Genes. 2013; 46(1): 54–62. https://doi.org/10.1007/s11262-012-0834-6 https://elibrary.ru/zxgixlMurphy M.E., Kariwa H., Mizutani T., Yoshimatsu K., Arikawa J., Takashima I. In vitro antiviral activity of lactoferrin and ribavirin upon hantavirus. Arch. Virol. 2000; 145(8): 1571–82. https://doi.org/10.1007/s007050070077 https://elibrary.ru/avrzyhMurphy M.E., Kariwa H., Mizutani T., Tanabe H., Yoshimatsu K., Arikawa J., et al. Characterization of in vitro and in vivo antiviral activity of lactoferrin and ribavirin upon Hantavirus. J. Vet. Med. Sci. 2001; 63(6): 637–45. https://doi.org/10.1292/jvms.63.637Jonsson C.B., Milligan B.G., Arterburn J.B. Potential importance of error catastrophe to the development of antiviral strategies for hantaviruses. Virus Res. 2005; 107(2): 195–205. https://doi.org/10.1016/j.virusres.2004.11.009 https://elibrary.ru/xrjnblChung D.H., Sun Y., Parker W.B., Arterburn J.B., Bartolucci A., Jonsson C.B. Ribavirin reveals a lethal threshold of allowable mutation frequency for Hantaan virus. J. Virol. 2007; 81(21): 11722–9. https://doi.org/10.1128/JVI.00874-07Sun Y., Chung D.H., Chu Y.K., Jonsson C.B., Parker W.B. Activity of ribavirin against Hantaan virus correlates with production of ribavirin-5′-triphosphate, not with inhibition of IMP dehydrogenase. Antimicrob. Agents Chemother. 2007; 51(1): 84–8. https://doi.org/10.1128/AAC.00790-06Nusshag C., Schreiber P., Uhrig J., Zeier M., Krautkrämer E. In-cell Western assay to quantify infection with pathogenic orthohantavirus Puumala virus in replication kinetics and antiviral drug testing. Virus Res. 2023; 337: 199230. https://doi.org/10.1016/j.virusres.2023.199230 https://elibrary.ru/jxfbisMayor J., Engler O., Rothenberger S. Antiviral efficacy of ribavirin and favipiravir against Hantaan virus. Microorganisms. 2021; 9(6): 1306. https://doi.org/10.3390/microorganisms9061306 https://elibrary.ru/txfjmeLee H.W., Seong I.W., Baek L.J., Lee J.I. The effects of Virazole to Hantaan virus infection in Apodemus agrarious. Korean J. Virol. 1981; 11: 13–9.Huggins J.W., Kim G.R., Brand O.M., McKee K.T. Jr. Ribavirin therapy for Hantaan virus infection in suckling mice. J. Infect. Dis. 1986; 153(3): 489–97. https://doi.org/10.1093/infdis/153.3.489Chung D.H., Västermark Å., Camp J.V., McAllister R., Remold S.K., Chu Y.K., et al. The murine model for Hantaan virus-induced lethal disease shows two distinct paths in viral evolutionary trajectory with and without ribavirin treatment. J. Virol. 2013; 87(20): 10997–1007. https://doi.org/10.1128/JVI.01394-13 https://elibrary.ru/yanwjfHuggins J.W., Hsiang C.M., Cosgriff T.M., Guang M.Y., Smith J.I., Wu Z.O., et al. Prospective, double-bind, concurrent, placebo-controlled clinical trial of intravenous ribavirin therapy of hemorrhagic fever with renal syndrome. J. Infect. Dis. 1991; 164(6): 1119–27. https://doi.org/10.1093/infdis/164.6.1119Malinin O.V., Platonov A.E. Insufficient efficacy and safety of intravenous ribavirin in treatment of haemorrhagic fever with renal syndrome caused by Puumala virus. Infect. Dis. (Lond.) 2017; 49(7): 514–20. https://doi.org/10.1080/23744235.2017.1293841 https://elibrary.ru/yvfxfbSamuels D.C. Mitochondrial AZT metabolism. IUBMB Life. 2006; 58(7): 403–8. https://doi.org/10.1080/15216540600791571Lim J.K., Wooten D., Siegel R., Cheung R.C. Amantadine in treatment of chronic hepatitis C virus infection? J. Viral Hepat. 2005; 12(5): 445–55. https://doi.org/10.1111/j.1365-2893.2005.00622.xNam J.H., Yu C.H., Hwang K.A., Ju Y.R. Real-time RT-PCR of Hantaan virus RNA used for the detection of virus response to antiviral drugs. Acta Virol. 2008; 52(1): 67–70.Moreli M.L., Marques-Silva A.C., Pimentel V.A., da Costa V.G. Effectiveness of the ribavirin in treatment of hantavirus infections in the Americas and Eurasia: a meta-analysis. Virusdisease. 2014; 25(3): 385–9. https://doi.org/10.1007/s13337-014-0219-7 https://elibrary.ru/vfahqpOgg M., Jonsson C.B., Camp J.V., Hooper J.W. Ribavirin protects Syrian hamsters against lethal hantavirus pulmonary syndrome-after intranasal exposure to Andes virus. Viruses. 2013; 5(11): 2704–20. https://doi.org/10.3390/v5112704Safronetz D., Haddock E., Feldmann F., Ebihara H., Feldmann H. In vitro and in vivo activity of ribavirin against Andes virus infection. PLoS One. 2011; 6(8): e23560. https://doi.org/10.1371/journal.pone.0023560Chung D.H., Kumarapperuma S.C., Sun Y., Li Q., Chu Y.K., Arterburn J.B., et al. Synthesis of 1-beta-D-ribofuranosyl-3-ethynyl-[1,2,4]triazole and its in vitro and in vivo efficacy against Hantavirus. Antiviral Res. 2008; 79(1): 19–27. https://doi.org/10.1016/j.antiviral.2008.02.003Furuta Y., Gowen B.B., Takahashi K., Shiraki K., Smee D.F., Barnard D.L. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res. 2013; 100(2): 446–54. https://doi.org/10.1016/j.antiviral.2013.09.015Furuta Y., Takahashi K., Kuno-Maekawa M., Sangawa H., Uehara S., Kozaki K., et al. Mechanism of action of T-705 against influenza virus. Antimicrob. Agents Chemother. 2005; 49(3): 981–6. https://doi.org/10.1128/AAC.49.3.981-986.2005Mendenhall M., Russell A., Juelich T., Messina E.L., Smee D.F., Freiberg A.N., et al. T-705 (favipiravir) inhibition of arenavirus replication in cell culture. Antimicrob. Agents Chemother. 2011; 55(2): 782–7. https://doi.org/10.1128/AAC.01219-10Smee D.F., Hurst B.L., Egawa H., Takahashi K., Kadota T., Furuta Y. Intracellular metabolism of favipiravir (T-705) in uninfected and influenza A (H5N1) virus-infected cells. J. Antimicrob. Chemother. 2009; 64(4): 741–6. https://doi.org/10.1093/jac/dkp274Furuta Y., Takahashi K., Fukuda Y., Kuno M., Kamiyama T., Kozaki K., et al. In vitro and in vivo activities of anti-influenza virus compound T-705. Antimicrob. Agents Chemother. 2002; 46(4): 977–81. https://doi.org/10.1128/AAC.46.4.977-981.2002Gowen B.B., Wong M.H., Jung K.H., Sanders A.B., Mendenhall M., Bailey K.W., et al. In vitro and in vivo activities of T-705 against arenavirus and bunyavirus infections. Antimicrob. Agents Chemother. 2007; 51(9): 3168–76. https://doi.org/10.1128/AAC.00356-07Ye C., Wang D., Liu H., Ma H., Dong Y., Yao M., et al. Corrigendum: an improved enzyme-linked focus formation assay revealed baloxavir acid as a potential antiviral therapeutic against hantavirus infection. Front. Pharmacol. 2020; 11: 201. https://doi.org/10.3389/fphar.2020.00201Vanderlinden E., Vrancken B., Van Houdt J., Rajwanshi V.K., Gillemot S., Andrei G., et al. Distinct effects of T-705 (Favipiravir) and Ribavirin on influenza virus replication and viral RNA synthesis. Antimicrob. Agents Chemother. 2016; 60(11): 6679–91. https://doi.org/10.1128/AAC.01156-16Safronetz D., Falzarano D., Scott D.P., Furuta Y., Feldmann H., Gowen B.B. Antiviral efficacy of favipiravir against two prominent etiological agents of hantavirus pulmonary syndrome. Antimicrob. Agents Chemother. 2013; 57(10): 4673–80. https://doi.org/10.1128/AAC.00886-13Munir N., Jahangeer M., Hussain S., Mahmood Z., Ashiq M., Ehsan F., et al. Hantavirus diseases pathophysiology, their diagnostic strategies and therapeutic approaches: a review. Clin. Exp. Pharmacol. Physiol. 2021; 48(1): 20–34. https://doi.org/10.1111/1440-1681.13403 https://elibrary.ru/btbzvbKataev V.E., Garifullin B.F. Antiviral nucleoside analogs. Chem. Heterocycl. Compd (NY). 2021; 57(4): 326–41. https://doi.org/10.1007/s10593-021-02912-8 https://elibrary.ru/lghyvfKumarapperuma S.C., Sun Y., Jeselnik M., Chung K., Parker W.B., Jonsson C.B., et al. Structural effects on the phosphorylation of 3-substituted 1-β-D-ribofuranosyl-1, 2, 4-triazoles by human adenosine kinase. Bioorg. Med. Chem. Lett. 2007; 17(11): 3203–7. https://doi.org/10.1016/j.bmcl.2007.03.018 https://elibrary.ru/jloobhMcDowell M., Gonzales S.R., Kumarapperuma S.C., Jeselnik M., Arterburn J.B., Hanley K.A. A novel nucleoside analog, 1-β-d-ribofuranosyl-3-ethynyl-[1, 2, 4]triazole (ETAR), exhibits efficacy against a broad range of flaviviruses in vitro. Antiviral Res. 2010; 87(1): 78–80. https://doi.org/10.1016/j.antiviral.2010.04.007Huggins J.W., Robins R.K., Canonico P.G. Synergistic antiviral effects of ribavirin and the C- nucleoside analogs tiazofurin and selenazofurin against togaviruses, bunyaviruses, and arenaviruses. Antimicrob. Agents Chemother. 1984; 26(4): 476–80. https://doi.org/10.1128/AAC.26.4.476Chung D.H., Strouse J.J., Sun Y., Arterburn J.B., Parker W.B., Jonsson C.B. Synthesis and anti-Hantaan virus activity of N1-3-fluorophenyl-inosine. Antiviral Res. 2009; 83(1): 80–5. https://doi.org/10.1016/j.antiviral.2009.03.007