Problems of VirologyProblems of VirologyВопросы вирусологии0507-40882411-2097Central Research Institute for Epidemiology20010.18821/0507-4088-2018-63-4-149-159REVIEWSОБЗОРЫMODERN ETHIOTROPIC CHEMOTHERAPY OF HERPESVIRUS INFECTIONS: ADVANCES, NEW TRENDS AND PERSPECTIVES. ALPHAHERPESVIRUSES (PART II)СОВРЕМЕННАЯ ЭТИОТРОПНАЯ ХИМИОТЕРАПИЯ ГЕРПЕСВИРУСНЫХ ИНФЕКЦИЙ: ДОСТИЖЕНИЯ, НОВЫЕ ТЕНДЕНЦИИ И ПЕРСПЕКТИВЫ. АЛЬФАГЕРПЕСВИРУСЫ (ЧАСТЬ II)AndronovaV. L.АндроноваВ. Л.
Russian Federation
andronova.vl@yandex.ruNational Research Center for Epidemiology and Microbiology named after the honorary academician N.F. GamaleyaФГБУ «Национальный исследовательский центр эпидемиологии и микробиологии имени почётного академика Н.Ф. Гамалеи» Минздрава России2008201863414915920012020Copyright ©; 2018, Andronova V.L.Copyright ©; 2018, Андронова В.Л.2018Andronova V.L.Андронова В.Л.https://creativecommons.org/licenses/by/4.0https://virusjour.crie.ru/jour/article/view/200

A key role in the treatment of herpesviral infections is played by modified nucleosides and their predecessors - acyclovir, its L-valine ester (valaciclovir) and famciclovir (prodrug of penciclovir). The biological activity of compounds of this class is determined by their similarity to natural nucleosides. After phosphorylation by viral thymidine kinase and then cell enzymes to the triphosphate forms, acyclovir and penciclovir inhibit the activity of viral DNA polymerase and synthesis of viral DNA. The increasing role of herpesvirus infections in human infectious pathology, as well as the development of drug resistance in viruses, mainly in patients with immunodeficiencies of various origins, necessitate the search for new compounds possessing anti-herpesvirus activity, using as a biological target not DNA polymerase, but other viral proteins and enzymes, unique or different from cellular proteins, performing similar functions.

Ключевую роль в лечении герпесвирусных инфекций играют модифицированные нуклеозиды и их предлекарства - ацикловир (АЦВ), его L-валиновый эфир (валацикловир) и фамцикловир (предлекарство пенцикловира - ПЦВ). Биологическая активность соединений этого класса определяется их сходством с природными нуклеозидами. После фосфорилирования вирусной тимидинкиназой и затем клеточными ферментами до трифосфатной формы АЦВ и ПЦВ ингибируют активность вирусной ДНК-полимеразы и синтез вирусной ДНК. Возрастающая роль герпесвирусных инфекций в инфекционной патологии человека, а также развитие лекарственной резистентности у вирусов, главным образом у пациентов с иммунодефицитами различного генеза, обусловливают необходимость поиска новых соединений, обладающих антигерпесвирусной активностью, использующих в качестве биомишени не ДНК-полимеразу, а другие вирусные белки и ферменты, уникальные или отличающиеся от клеточных белков, выполняющих аналогичные функции. Целью данной работы были поиск научной литературы, посвящённой описанию новых соединений с альтернативным механизмом действия, с помощью международных баз данных (PubMed, MedLine, РИНЦ и других) и проведение анализа собранных данных о соединениях, потенциально пригодных для создания на их основе лекарственных противогерпетических препаратов.

reviewherpes simplex virusvaricella zoster virusdrugобзорвирус герпеса простоговирус варицелла зостерантивирусный агентлекарственный препаратаntiviral agentИнформационный бюллетень ВОЗ. Вирус простого герпеса. Available at: http://www.who.int/mediacentre/factsheets/fs400/ru/Elion G.B. Acyclovir discovery, mechanism of action and selectivity. J. Med. Virol. 1993; (Suppl. 1): 2-6. PMID: 8245887Frobert E., Burrel S., Ducastelle-Lepretre S., Billaud G., Ader F., Casalegno J.S., et al. Resistance of herpes simplex viruses to acyclovir: an update from a ten-year survey in France. Antiviral. Res. 2014; 111: 36-41. PMID: 25218782 DOI: 10.1016/j.antiviral.2014.08.013ВОЗ. Значимость устойчивости к противомикробным препаратам для общественного здравоохранения. Available at: http://www.who.int/drugresistance/AMR_Importance/ru/Gilbert C., Bestman-Smith J., Boivin G. Resistance of herpesviruses to antiviral drugs: clinical impacts and molecular mechanisms. Drug Resist. Updat. 2002; 5(2): 88-114. PMID: 12135584Frobert E., Cortay J.C., Ooka T., Najioullah F., Thouvenot D., Lina B., et al. Genotypic detection of acyclovir-resistant HSV-1: characterization of 67 ACV-sensitive and 14 ACV-resistant viruses. Antiviral Res. 2008; 79(1): 28-36. PMID: 18336925 DOI: 10.1016/j.antiviral.2008.01.153Spear P.G., Eisenberg R.J., Cohen G.H. Three classes of cell surface receptors for alphaherpesvirus entry. Virology. 2000; 275(1): 1-8. PMID: 11017782Keller M.J., Tuyama A., Carlucci M.J., Herold B.C. Topical microbicides for the prevention of genital herpes infection. J. Antimicrob. Chemother. 2005; 55(4): 420-3. PMID: 15743896 DOI: 10.1093/jac/dki056Price C.F., Tyssen D., Davie A., Evans S., Lewis G.R., Xia S., et al. SPL7013 Gel (VivaGel®) retains potent HIV-1 and HSV-2 inhibitory activity following vaginal administration in humans. PLoS One. 2011; 6(9): e24095. PMID: 21935377 PMCID: PMC3174146 DOI: 10.1371/journal.pone.0024095Smith C.C., Peng T., Kulka M., Aurelian L. The PK domain of the large subunit of herpes simplex virus type 2 ribonucleotidereductase (ICP10) is required for immediate-early gene expression and virus growth. J. Virol. 1998; 72(11): 9131-41. PMID: 9765459 PMCID: PMC110331Idowu A.D., Fraser-Smith E.B., Poffenberger K.L., Herman R.C. Deletion of the herpes simplex virus type 1 ribonucleotidereductasegene alters virulence and latency in vivo. Antiviral Res. 1992; 17(2): 145-56. PMID: 1313220Bonneau A.M., Kibler P., White P., Bousquet C., Dansereau N., Cordingley M.G. Resistance of herpes simplex virus type 1 to peptidomimetic ribonucleotidereductase inhibitors: selection and characterization of mutant isolates. J. Virol. 1996; 70(2): 787-93. PMID: 8551616Duan J., Liuzzi M., Paris W., Lambert M., Lawetz C., Moss N., et al. Antiviral activity of a selective ribonucleotidereductase inhibitor against acyclovir-resistant herpes simplex virus type 1 in vivo. Antimicrob. Agents Chemother. 1998; 42(7): 1629-35. PMID: 9660995Koff A., Schwedes J.F., Tegtmeyer P. Herpes simplex virus origin-binding protein (UL9) loops and distorts the viral replication origin. J. Virol. 1991; 65(6): 3284-92. PMID: 1851878 PMCID: PMC240986Андронова В.Л., Гроховский С.Л., Суровая А.Н., Гурский Г.В., Галегов Г.А. Антигерпетическая активность димерных производных нетропсина. Доклады Академии наук. 2001; 380(4): 548-51.Андронова В.Л., Гроховский С.Л., Суровая А.Н., Гурский Г.В., Галегов Г.А. Действие димерного аналога нетропсина 15Lys-bis-Nt и ацикловира на репродукцию вируса простого герпеса. Поиск вариантов вируса герпеса с лекарственной устойчивостью к 15Lys-bis-Nt и ацикловиру. Доклады Академии наук. 2015; 460(5): 595-600.Wemmer D.E. Ligands recognizing the minor groove of DNA: development and applications. Biopolymers. 1999-2000; 52(4): 197-211.Bazhulina N.P., Surovaya A.N., Gursky Y.G., Andronova V.L., Moiseeva E.D., Nikitin C.A., et al. Complex of the herpes simplex virus type 1 origin binding protein UL9 with DNA as a platform for the design of a new type of antiviral drugs. J. Biomol. Struct. Dyn. 2014; 32(9): 1456-73. PMID: 23879454 DOI: 10.1080/07391102.2013.820110Андронова В.Л., Гроховский С.Л., Суровая А.Н., Гурский Г.В., Галегов Г.А. Антигерпетическая активность комбинаций производных нетропсина с модифицированными нуклеозидами и фосфоноуксусной кислотой на модели вируса герпеса простого первого типа в культуре клеток Vero. Доклады Академии наук. 2005; 400(6): 822-6ChemlDplus. A Toxnet Database. Netropsin. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/1438-30-8Андронова В.Л., Гроховский С.Л., Суровая А.Н., Гурский Г.В., Галегов Г.А. Действие димерных производных нетропсина и их комбинаций с ацикловиром на герпесвирусную инфекцию мышей. Доклады Академии наук. 2007; 43(6): 830-4.Андронова В.Л., Гроховский С.Л., Суровая А.Н., Гурский Г.В., Дерябин П.Г., Львов Д.К. и др. Оценка активности производных бис-нетропсина на модели экспериментального кожного герпеса морских свинок. Вопросы вирусологии. 2013; 58(1): 32-5.Whitley R.J., Prichard M. A novel potential therapy for HSV. N. Engl. J. Med. 2014; 370(3): 273-4. DOI: 10.1056/NEJMe1313982.Field H.J., Huang M.L., Lay E.M., Mickleburgh I., Zimmermann H., Birkmann A. Baseline sensitivity of HSV-1 and HSV-2 clinical isolates and defined acyclovir-resistant strains to the helicase-primase inhibitor pritelivir. Antiviral Res. 2013; 100(2): 297-9. PMID: 24021190 DOI: 10.1016/j.antiviral.2013.08.024/Betz U. A., Fischer R., Kleymann G., Hendrix M., Rubsamen-Waigmann H. Potent in vivo antiviral activity of the herpes simplex virus primase-helicase inhibitor BAY 57-1293. Antimicrob. Agents Chemother. 2002; 46(6): 1766-72. PMID: 12019088 PMCID: PMC127257Kaufman H.E., Varnell E.D., Gebhardt B.M., Thompson H.W., Atwal E., Rübsamen-Waigmann H., et al. Efficacy of a helicase-primase inhibitor in animal models of ocular herpes simplex virus type 1 infection. J. Ocul. Pharmacol. Ther. 2008; 24(1): 34-42. PMID: 18201137 PMCID: PMC2365309 DOI: 10.1089/jop.2007.0084Sukla S., Biswas S., Birkmann A., Lischka P., Zimmermann H., Field H.J. Mismatch primer-based PCR reveals that helicase-primase inhibitor resistance mutations pre-exist in herpes simplex virus type 1 clinical isolates and are not induced during incubation with the inhibitor. J. Antimicrob. Chemother. 2010; 65(7): 1347-52. PMID: 20453068 PMCID: PMC2835512 DOI: 10.1093/jac/dkq135Biswas S., Kleymann G., Swift M., Tiley L.S., Lyall J., Aguirre-Hernández J., et al. A single drug-resistance mutation in HSV-1 UL52 primase points to a difference between two helicase-primase inhibitors in their mode of interaction with the antiviral target. J. Antimicrob. Chemother. 2008; 61(5): 1044-7. PMID: 18299638 DOI: 10.1093/jac/dkn057Davison A.J., Scott J.E. Complete DNA Sequence of Varicella-Zoster Virus. J. Gen. Virol. 1986; 67(Pt. 9): 1759-816. PMID: 3018124 DOI: 10.1099/0022-1317-67-9-1759Wald A., Corey L., Timmler B., Magaret A., Warren T., Tyring S., et al. Helicase-primase inhibitor pritelivir for HSV-2 infection. N. Engl. J. Med. 2014; 370(3): 201-10. PMID: 24428466 DOI: 10.1056/NEJMoa1301150Walt A., Timmler B., Magaret A., Warren T., Tyring S., Johnston C., et al. Effect of pritelivir compared with valacyclovir on genital HSV-2 shedding in patients with frequent recurrences: a randomized clinical trial. JAMA. 2016; 316(23): 2495-503. DOI: 10.1001/jama.2016.18189Crute J.J., Grygon C.A., Hargrave K.D., Simoneau B., Faucher A.M., Bolger G., et al. Herpes simplex virus helicase-primase inhibitors are active in animal models of human disease. Nat. Med. 2002; 8(4): 386-91. PMID: 11927945 DOI: 10.1038/nm0402-386Duan J., Liuzzi M., Paris W., Liard F., Browne A., Dansereau N., et al. Oral bioavailability and in vivo efficacy of the helicase-primase inhibitor BILS 45 BS against acyclovir-resistant herpes simplex virus type 1. Antimicrob. Agents Chemother. 2003; 47(6): 1798-804. PMID: 12760851 PMCID: PMC155846Biswas S., Field H.J. Herpes simplex virus helicase-primase inhibitors: resent findings from the study of drug resistance mutations. Antivir. Chem. Chemother. 2008; 19(1): 1-6. PMID: 18610552 DOI: 10.1177/095632020801900101Chono K., Katsumata K., Kontani T., Kobayashi M., Sudo K., Yokota T., et al. ASP2151, a novel helicase-primase inhibitor, possesses antiviral activity against varicella-zoster virus and herpes simplex virus types 1 and 2. J. Antimicrob. Chemother. 2010; 65(8): 1733-41. PMID: 20534624 DOI: 10.1093/jac/dkq198Chono K., Katsumata K., Suzuki H., Shiraki K. Synergistic activity of amenamevir (ASP2151) with nucleoside analogs against herpes simplex virus types 1 and 2 and varicella-zoster virus. Antiviral Res. 2013; 97(2): 154-60. PMID: 23261844 DOI: 10.1016/j.antiviral.2012.12.006Katsumata K., Chono K., Sudo K., Shimizu Y., Kontani T., Suzuki H. Effect of ASP2151, a herpesvirus helicase-primase inhibitor, in a guinea pig model of genital herpes. Molecules. 2011; 16(9): 7210-23. PMID: 21869749 DOI: 10.3390/molecules16097210Tyring S., Wald A., Zadeikis N., Dhadda S., Takenouchi K., Rorig R. ASP2151 for the treatment of genital herpes: a randomized, double-blind, placebo- and valacyclovir-controlled, dose-finding study. J. Infect. Dis. 2012; 205(7): 1100-10. PMID: 22351940 DOI: 10.1093/infdis/jis019Weinheimer S.P., McCann P.J., O’Boyle D.R., Stevens J.T., Boyd B.A., Drier D.A., et al. Autoproteolysis of herpes simplex virus type 1 protease releases an active catalytic domain found in intermediate capsid particles. J. Virol. 1993; 67(10): 5813-22. PMID: 8396657 PMCID: PMC237999Chen P., Tsuge H., Almassy R.J., Gribskov C.L., Katoh S., Vanderpool D.L., et al. Structure of the human cytomegalovirus protease catalytic domain reveals a novel serine protease fold and catalytic triad. Cell. 1996; 86(5): 835-43. PMID: 8797829DiIanni C.L., Stevens J.T., Bolgar M., O’Boyle D.R., Weinheimer S.P., Colonno R.J. Identification of the serine residue at the active site of the herpes simplex virus type 1 protease. J. Biol. Chem. 1994; 269(17): 12672-6. PMID: 8175677Qiu X., Janson C.A., Culp J.S., Richardson S.B., Debouck C., Smith W.W., et al. Crystal structure of varicella-zoster virus protease. Proc. Natl. Acad. Sci. USA. 1997; 94(7): 2874-9. PMID: 9096314 PMCID: PMC20290Matsumoto M., Misawa S., Chiba N., Takaku H., Hayashi H. Selective nonpeptidic inhibitors of herpes simplex virus type 1 and human cytomegalovirus proteases. Biol. Pharm. Bull. 2001; 24(3): 236-41. PMID: 11256477Budihas S.R., Gorshkova I., Gaidamakov S., Wamiru A., Bona M.K., Parniak M.A., et al. Selective inhibition of HIV-1 reverse transcriptase-associated ribonuclease H activity by hydroxylated tropolones. Nucleic. Acids Res. 2005; 33(4): 1249-56. PMID: 15741178 PMCID: PMC552956 DOI: 10.1093/nar/gki268Chung S., Himmel D.M., Jiang J.K., Wojtak K., Bauman J.D., Rausch J.W., et al. Synthesis, activity, and structural analysis of novel α-hydroxytropolone inhibitors of human immunodeficiency virus reverse transcriptase-associated ribonuclease H. J. Med. Chem. 2011; 54(13): 4462-73. PMID: 21568335 PMCID: PMC3133734 DOI: 10.1021/jm2000757Tavis J.E., Wang H., Tollefson A.E., Ying B., Korom M., Cheng X., et al. Inhibitors of nucleotidyltransferase superfamily enzymes suppress herpes simplex virus replication. Antimicrob. Agents Chemother. 2014; 58(12): 7451-61. PMID: 25267681 PMCID: PMC4249532 DOI: 10.1128/AAC.03875-14Ireland P.J., Tavis J.E., D’Erasmo M.P., Hirsch D.R., Murelli R.P., Cadiz M.M., et al. Synthetic α-hydroxytropolones inhibit replication of wild-type and acyclovir-resistant herpes simplex viruses. Antimicrob. Agents Chemother. 2016; 60(4): 2140-9. DOI: 10.1128/AAC.02675-15Masaoka T., Zhao H., Hirsch D.R., D’Erasmo M.P., Meck C., Varnado B., et al. Characterization of the C-Terminal Nuclease Domain of Herpes Simplex Virus pUL15 as a Target of Nucleotidyltransferase Inhibitors. Biochemistry. 2016; 55(5): 809-19. DOI: 10.1021/acs.biochem.5b01254.Nadal M., Mas P.J., Blanco A.G., Arnan C., Solà M., Hart D.J., et al. Structure and inhibition of herpesvirus DNA packaging terminase nuclease domain. Proc. Natl. Acad. Sci. USA. 2010; 107(37): 16078-83. PMID: 20805464 PMCID: PMC2941324 DOI: 10.1073/pnas.1007144107Selvarajan Sigamani S., Zhao H., Kamau Y.N., Baines J.D., Tang L. The structure of the herpes simplex virus DNA-packaging terminase pUL15 nuclease domain suggests an evolu-tionary lineage among eukaryotic and prokaryotic viruses. J. Virol. 2013; 87(12): 7140-8. PMID: 23596306 PMCID: PMC3676077 DOI: 10.1128/JVI.00311-13Bryant K.F., Yan Z., Dreyfus D.H., Knipe D.M. Identification of a divalent metal cation binding site in herpes simplex virus 1 (HSV-1) ICP8 required for HSV replication. J. Virol. 2012; 86(12): 6825-34. PMID: 23596306 PMCID: PMC3676077 DOI: 10.1128/JVI.00311-13Reuven N.B., Staire A.E., Myers R.S., Weller S.K. The herpes simplex virus type 1 alkaline nuclease and single-stranded DNA binding protein mediate strand exchange in vitro. J. Virol. 2003; 77(13): 7425-33. PMID: 12805441 PMCID: PMC164775Yan Z., Bryant K.F., Gregory S.M., Angelova M., Dreyfus D.H, Zhao X.Z., et al. HIV integrase inhibitors block replication of alpha-, beta-, and gammaherpesviruses. MBio. 2014; 5(4): e01318-14. DOI: 10.1128/mBio.01318-14Trus B.L., Cheng N., Newcomb W.W., Homa F.L., Brown J.C., Steven A.C. Structure and polymorphism of the UL6 portal protein of herpes simplex virus type 1. J. Virol, 2004; 78(22): 12668-71. PMID: 15507654 PMCID: PMC525097 DOI: 10.1128/JVI.78.22.12668-12671.2004vanZeijl M., Fairhurst J., Jones T.R., Vernon S.K., Morin J., La Rocque J., et al. Novel class of thiourea compounds that inhibit herpes simplex virus type 1 DNA cleavage and encapsidation: resistance maps to the UL6 gene. J. Virol. 2000; 74(19): 9054-61.PMID: 10982350 PMCID: PMC102102Schang L.M., Bantly A., Schaffer P.A. Explant-induced reactivation of herpes simplex virus occurs in neurons expressing nuclear cdk2 and cdk4. J. Virol. 2002; 76(15): 7724-35. PMID: 12097586 PMCID: PMC136347Schang L.M., Rosenberg A., Schaffer P.A. Roscovitine, a specific inhibitor of cellular cyclin-dependent kinases, inhibits herpes simplex virus DNA synthesis in the presence of viral early proteins. J. Virol. 2000; 74(5): 2107-20. PMID: 10666240 PMCID: PMC111691Greco A., Callé A., Morfin F., Thouvenot D., Cayre M., Kindbeiter K., et al. S-adenosyl methionone decarboxylase activity is required for the outcome of herpes simplex virus type 1 infection and represents a new potential therapeutic target. FASEB J. 2005; 19(9): 1128-30. PMID: 15863396 DOI: 10.1096/fj.04-2108fjeFrancke B. Cell-free synthesis of herpes simplex virus DNA: the influence of polyamines. Biochemistry. 1978; 17(25): 5494-9. PMID: 215202Goodell J.R., Madhok A.A., Hiasa H., Ferguson D.M. Synthesis and evaluation of acridine- and acridone-based anti-herpes agents with topoisomerase activity. Bioorg. Med. Chem. 2006; 14(16): 5467-80. PMID: 16713270 DOI: 10.1016/j.bmc.2006.04.044