Problems of VirologyProblems of VirologyВопросы вирусологии0507-40882411-2097Central Research Institute for Epidemiology19310.18821/0507-4088-2018-63-3-106-114REVIEWSОБЗОРЫMODERN ETHIOTROPIC CHEMOTHERAPY OF HERPESVIRUS INFECTIONS: ADVANCES, NEW TRENDS AND PERSPECTIVES. ALPHAHERPESVIRINAE (part I)СОВРЕМЕННАЯ ЭТИОТРОПНАЯ ХИМИОТЕРАПИЯ ГЕРПЕСВИРУСНЫХ ИНФЕКЦИЙ: ДОСТИЖЕНИЯ, НОВЫЕ ТЕНДЕНЦИИ И ПЕРСПЕКТИВЫ. АЛЬФАГЕРПЕСВИРУСЫ (ЧАСТЬ I)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 России2006201863310611420012020Copyright ©; 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/193

Modern therapy of infections caused by alpha-herpesviruses is based on drugs belonging to the class of modified nucleosides (acyclovir) and their metabolic progenitors - valine ester of acyclovir and famciclovir (prodrug of penciclovir). The biological activity of these compounds is determined by the similarity of their structure to natural nucleosides: modified nucleosides compete with natural nucleosides for binding to DNA-polymerase and, due to their structural features, inhibit its activity. However, the emergence of variants of viruses resistant to the antiviral drugs available in the arsenal of modern medicine necessitates the search for new compounds able of effectively inhibiting the reproduction of viruses. These compounds should be harmless to the macroorganisms, convenient to use, and overcoming the drug resistance barrier in viruses. The search for literature in international databases (PubMed, MedLine, RINC, etc.) in order to obtain information on promising developments that open new possibilities for treating herpesvirus infection and subsequent analysis of the collected data made it possible to determine not only the main trends in the search for new antiviral agents, but also to provide information on the compounds most promising for the development of anti-herpesvirus drugs.

Современная терапия инфекций, вызываемых альфагерпесвирусами, базируется на препаратах, относящихся к классу модифицированных нуклеозидов (ацикловир), и их метаболических предшественниках (валиновый эфир ацикловира и фамцикловир (предшественник пенцикловира)). Биологическая активность этих соединений определяется сходством их структуры с природными нуклеозидами: модифицированные нуклеозиды конкурируют с природными за связывание с ДНК-полимеразой и благодаря структурным особенностям ингибируют её активность. Однако появление вариантов вирусов, резистентных к имеющимся в арсенале современной медицины антивирусным препаратам, обусловливает необходимость поиска новых соединений, способных эффективно ингибировать репродукцию вируса, безвредных для макроорганизма, удобных в применении, преодолевающих барьер лекарственной устойчивости у вирусов. Поиск литературы в международных базах данных (PubMed, MedLine, РИНЦ и других) с целью получения информации о перспективных разработках, открывающих новые возможности воздействия на герпесвирусную инфекцию, и последующий анализ собранных данных позволили не только определить основные тенденции поиска новых антивирусных агентов, но и привести информацию о соединениях, наиболее перспективных для создания лекарственных антигерпесвирусных препаратов.

reviewherpes simplex virusvirus varicella zosterantivirus agent, drugобзорвирус герпеса простоговирус варицелла зостерантивирусный агентлекарственный препаратВирус простого герпеса. Информационный бюллетень ВОЗ. Available at: http://www.who.int/mediacentre/factsheets/fs400/ru/De Donno A., Kuhdari P., Guido M., Rota M.C., Bella A., Brignole G., et al. Has VZV epidemiology changed in Italy? Results of a seroprevalence study. Hum. Vaccin. Immunother. 2017; 13(2): 385-90.Perez-Farinos N., Garcia-Comas L., Ramirez-Fernandez R., Sanz J.C., Barranco D., Garcia-Fernandez C., et al. Seroprevalence of antibodies to varicella-zoster virus in Madrid (Spain) in the absence of vaccination. Cent. Eur. J. Public. Health. 2008; 16(1): 41-4.ВИЧ/СПИД. Информационный бюллетень ВОЗ. Available at: http://www.who.int/mediacentre/factsheets/fs360/ru/Elion G.B. Acyclovir discovery, mechanism of action and selectivity. J. Med. Virol. 1993; (Suppl. 1): 2-6.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.Значимость устойчивости к противомикробным препаратам для общественного здравоохранения. Available at: http://www.who.int/drugresistance/AMR_Importance/ru/Leary J.J., Wittrock R., Sarisky R.T., Weinberg A., Levin M.J. Susceptibilities of herpes simplex viruses to penciclovir and acyclovir in eight cell lines. Antimicrob. Agents Chemother., 2002; 46(3): 762-8.Morfin F., Thouvenot D., De Turenne-Tessier M., Lina B., Aymard M., Ooka T. Phenotypic and genetic characterization of thymidine kinase from clinical strains of varicella-zoster virus resistant to acyclovir. Antimicrob. Agents Chemother., 1999; 43(10): 2412-6.Coen N., Duraffour S., Haraguchi K., Balzarini J., van den Oord J.J., Snoeck R., et al. Antiherpesvirus activities of two novel 4’-thiothymidine derivatives, KAY-2-41 and KAH-39-149, are dependent on viral and cellular thymidine kinases. Antimicrob. Agents Chemother. 2014; 58(8): 4328-40.Neyts J., Andrei G., De Clercq E. The novel immunosuppressive agent mycophenolate mofetil markedly potentiates the antiherpesvirus activities of acyclovir, ganciclovir, and penciclovir in vitro and in vivo. Antimicrob. Agents Chemother. 1998; 42(2): 216-22.Weinberg A., Bate B.J., Masters H.B., Schneider S.A., Clark J.C., Wren C.G., et al. In vitro activities of penciclovir and acyclovir against herpes simplex virus types 1 and 2. Antimicrob. Agents Chemother. 1992; 36(9): 2037-8.Birch C.J., Tyssen D.P., Tachedjian G., Doherty R., Hayes K., Mijch A., et al. Clinical effects and in vitro studies of trifluorothymidine combined with interferon-alpha for treatment of drug-resistant and -sensitive herpes simplex virus infections. J. Infect. Dis. 1992; 166(1): 108-12.Costin D., Dogaru M., Popa A., Cijevschi I. Trifluridine therapy in herpetic in keratitis. Rev. Med. Chir. Soc. Med. Nat. Iasi. 2004; 108(2): 409-12.Turner L.D., Beckingsale P. Acyclovir-resistant herpetic keratitis in a solid-organ transplant recipient on systemic immunosuppression. Clin. Ophthalmol. 2013; 7: 229-32.De Clercq E. Discovery and development of BVDU (brivudin) as a therapeutic for the treatment of herpes zoster. Biochem. Pharmacol., 2004; 68(12): 2301-15.De Clercq E., Sakuma T., Baba M., Pauwels R., Balzarini J., Rosenberg I., et al. Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines. Antiviral Res. 1987; 8(5-6): 261-72.Steingrimsdottir H., Gruber A., Palm C., Grimfors G., Kalin M., Eksborg S. Bioavail-ability of aciclovir after oral administration of aciclovir and its prodrug valaciclovir to patients with leukopenia after chemotherapy. Antimicrob. Agents Chemother. 2000; 44(1): 207-9.Purifoy D.J., Beauchamp L.M., de Miranda P., Ertl P., Lacey S., Roberts G., et al. Review of research leading to new anti-herpesvirus agents in clinical development: Valaciclovir hydrochloride (256U, the L-valyl ester of acyclovir) and 882C, a specific agent for varicella zoster virus. J. Med. Virol. 1993; (Suppl. 1): 139-45.Katragadda S., Jain R., Kwatra D., Hariharan S., Mitra A.K. Pharmacokinetics of amino acid ester prodrugs of acyclovir after oral administration: interaction with the transporters on Caco-2 cells. Int. J. Pharm. 2008; 362(1-2): 93-101.Hughes P.M., Mitra A.K. Effect of acylation on the ocular disposition of acyclovir. II: Corneal permeability and anti-HSV 1 activity of 2’-esters in rabbit epithelial keratitis. J. Ocul. Pharmacol. 1993; 9(4): 299-309.Hatanaka T., Haramura M., Fei Y.J., Miyauchi S., Bridges C.C., Ganapathy P.S., et al. Transport of amino acid-based prodrugs by the Na+- and Cl(-) -coupled amino acid transporter ATB0,+ and expression of the transporter in tissues amenable for drug delivery. J. Pharmacol. Exp. Ther., 2004; 308(3): 1138-47.Katragadda S., Gunda S., Hariharan S., Mitra A.K. Ocular pharmacokinetics of acyclovir amino acid ester prodrugs in the anterior chamber: evaluation of their utility in treating ocular HSV infections. Int. J. Pharm. 2008; 359(1-2): 15-24.Anand B.S., Hill J.M., Dey S., Maruyama K., Bhattacharjee P.S., Myles M.E., et al. In vivo antiviral efficacy of a dipeptide acyclovir prodrug, val-val-acyclovir, against HSV-1 epithelial and stromal keratitis in the rabbit eye model. Invest. Ophthalmol. Vis. Sci. 2003; 44(6): 2529-34.Андронова В.Л., Ясько М.В., Куханова М.К., Галегов Г.А., Скоблов Ю.С., Кочетков С.Н. Антигерпесвирусная эффективность фосфита ациклогуанозина, преодолеваю-щеего барьер лекарственной устойчивости. Acta Naturae, 2016; 8(1): 74-81Skoblov Y.S., Karpenko I.L., Jasko M.V., Kukhanova M.K., Andronova V.L., Galegov G.A., et al. Cell metabolism of acyclovir phosphonate derivatives and antiherpesvirus activity of their combinations with alpha2-interferon. Chem. Biol. Drug Des. 2007; 69(6): 429-34.Gus’kova A.A., Skoblov M.Y., Korovina A.N., Karpenko I.L., Kukhanova M.K., Andronova V.L., et al. Antiherpetic properties of acyclovir 5’-hydrogenphosphonate and the mutation analysis of herpes virus resistant strains. Chem. Biol. Drug Des. 2009; 74(4): 382-9.Banker A.S., De Clercq E., Taskintuna I., Keefe K.S., Bergeron-Lynn G., Freeman W.R. Influence of intravitreal injections of HPMPC and related nucleoside analogs on intra-ocular pressure in guinea pig eyes. Invest. Ophthalmol. Vis. Sci. 1998; 39(7): 1233-42.Cheng L., Hostetler K.Y., Lee J., Koh H.J., Beadle J.R., Bessho K., et al. Characterization of a Novel Intraocular Drug-Delivery System Using Crystalline Lipid Antiviral Prodrugs of Ganciclovir and Cyclic Cidofovir. Invest. Ophthalmol. Vis. Sci. 2004; 45(11): 4138-44.Lowe D.M., Alderton W.K., Ellis M.R., Parmar V., Miller W.H., Roberts G.B., et al. Mode of action of (R)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine against herpesviruses. Antimicrob. Agents Chemother. 1995; 39(8): 1802-8.Abele G., Karlström A., Harmenberg J., Shigeta S., Larsson A., Lindborg B., et al. Inhibiting effect of (RS)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine on varicella-zoster virus replication in cell culture. Antimicrob. Agents Chemother. 1987; 31(1): 76-80.Ng T.I., Shi Y., Huffaker H.J., Kati W., Liu Y., Chen C.M., et al. Selection and characterization of varicella-zoster virus variants resistant to (R)-9-[4-hydroxy-2-(hydroxymethy)butyl]-guanine. Antimicrob. Agents Chemother. 2001; 45(6): 1629-36.Tyring S.K., Plunkett S., Scribner A.R., Broker R.E., Herrod J.N., Handke L.T., et al. Valomaciclovir versus valacyclovir for the treatment of acute herpes zoster in immunocompetent adults: a randomized, double-blind, active-controlled trial. J. Med. Virol. 2012; 84(8): 1224-32.McGuigan C., Barucki H., Carangio A., Blewett S., Andrei G., Snoeck R., et al. Highly potent and selective inhibition of varicella-zoster virus by bicyclic furopyrimidine nucleosides bearing an aryl side chain. J. Med. Chem. 2000; 43(26): 4993-7.McGuigan C., Pathirana R.N., Migliore M., Adak R., Luoni G., Jones A.T., et al. Preclinical development of bicyclic nucleoside analogues as potent and selective inhibitors of varicella zoster virus. J. Antimicrob. Chemother. 2007; 60(6): 1316-30.Sienaert R., Naesens L., Brancale A., De Clercq E., McGuigan C., Balzarini J. Specific recognition of the bicyclic pyrimidine nucleoside analogs, a new class of highly potent and selective inhibitors of varicella-zoster virus (VZV), by the VZV-encoded thymidine kinase. Mol. Pharmacol. 2002; 61(2): 249-54.Pentikis H.S., Matson M., Atiee G., Boehlecke B., Hutchins J.T., Patti J.M., et al. Pharmacokinetics and safety of FV-100, a novel oral anti-herpes zoster nucleoside analogue, administered in single and multiple doses to healthy young adult and elderly adult volunteers. Antimicrob. Agents Chemother. 2011; 55(6): 2847-54.Descamps J., Sehgal R.K., De Clercq E., Allaudeen H.S. Inhibitory effect of E-5-(2-bromovinyl)-1-beta-D-arabinofuranosyluracil on herpes simplex virus replication and DNA synthesis. J. Virol. 1982; 43(1): 332-6.Machida H., Nishitani M., Suzutani T., Hayashi K. Different antiviral potencies of BV-araU and related nucleoside analogues against herpes simplex virus type 1 in human cell lines and Vero cells. Microbiol. Immunol. 1991; 35(11): 963-73.Wallace M.R., Chamberlin C.J., Sawyer M.H., Arvin A.M., Harkins J., LaRocco A., et al. Treatment of adult varicella with sorivudine: a randomized, placebo-controlled trial. J. Infect. Dis. 1996; 174(2): 249-55.Okuda H., Ogura K., Kato A., Takubo H., Watabe T. A possible mechanism of eighteen patient deaths caused by interactions of sorivudine, a new antiviral drug, with oral 5-fluorouracil prodrugs. J. Pharmacol. Exp. Ther. 1998; 287(2): 791-9.Braitman A., Swerdel M.R., Olsen S.J., Tuomari A.V., Lynch J.S., Blue B., et al. Evaluation of SQ 34,514: pharmacokinetics and efficacy in experimental herpesvirus infections in mice. Antimicrob. Agents Chemother. 1991; 35(7): 1464-8.Koyano S., Suzulani Т., Yoshida I., Azuma M. Analysis of phosphorylation pathways of antiherpesvirus nucleosides by varicella-zoster virus-specific enzymes. Antimicrob. Agents Chemother. 1996; 40(4): 920-3.Ying C., De Clercq E., Neyts J. Lamivudine, adefovir and tenofovir exhibit long-lasting anti-hepatitis B virus activity in cell culture. J. Viral Hepat. 2000; 7(1): 79-83.Tenney D.J., Yamanaka G., Voss S.M., Cianci C.W., Tuomari A.V., Sheaffer A.K., et al. Lobucavir is phosphorylated in human cytomegalovirus-infected and uninfected cells and inhibits the viral DNA polymerase. Antimicrob. Agents Chemother. 1997; 41(12): 2680-5.Petty B.G., Saito H., Summerill R.S., Burgee H., McDowell J., Stewart M.B. Pharmacokinetics and bioavailabilily of cygalovir (BMS-180194) in asymptomatic HIV- and CMV-seropositive volunteers. Antiviral Res. 1994; 23 (Suppl. 1): 44.Shiota H., Nitta K., Naito T., Mimura Y., Maruyama T. Clinical evaluation of carbocyclic oxetanocin G eyedrops in the treatment of herpes simplex corneal ulcers. Br. J. Ophthalmol. 1996; 80(5): 413-5.Brideau R.J., Knechtel M.L., Huang A., Vaillancourt V.A., Vera E.E., Oien N.L., et al. Broad-spectrum antiviral activity of PNU-183792, a 4-oxo-dihydroquinoline, against human and animal herpesviruses. Antiviral Res. 2002; 54(1): 19-28.Schnute M.E., Cudahy M.M., Brideau R.J., Homa F.L., Hopkins T.A., Knechtel M.L., et al. 4-Oxo-4,7-dihydrothieno[2,3-b]pyridinesasnon-nucleoside inhibitors of human cytome-galovirus and related herpesvirus polymerases. J. Med. Chem. 2005; 48(18): 5794-804.Thomsen D.R., Oien N.L., Hopkins T.A., Knechtel M.L., Brideau R.J., Wathen M.W., et al. Amino acid changes within conserved region III of the herpes simplex virus and human cytomegalovirus DNA polymerases confer resistance to 4-oxo-dihydroquinolines, a novel class of herpesvirus antiviral agents. J. Virol. 2003; 77(3): 1868-76.Gottlieb J., Challberg M.D. Interaction of herpes simplex virus type 1 DNA polymerase and the UL42 accessory protein with a model primer template. J. Virol. 1994; 68(8): 4937-45.Loregian A., Papini E., Satin B., Marsden H.S., Hirst T.R., Palù G. Intranuclear delivery of an antiviral peptide mediated by the B subunit of Escherichia coli heat-labile enterotoxin. Proc. Natl. Acad. Sci. USA. 1999; 96(9): 5221-6.Zuccola H.J., Filman D.J., Coen D.M., Hogle J.M. The crystal structure of an unusual processivity factor, herpes simplex virus UL42, bound to the C terminus of its cognate polymerase. Mol. Cell. 2000; 5(2): 267-78.Bridges K.G., Chow C.S., Coen D.M. Identification of crucial hydrogen-bonding residues for the interaction of herpes simplex virus DNA polymerase subunits via peptide display, mutational, and calorimetric approaches. J. Virol. 2001; 75(11): 4990-8.Pilger B.D., Cui C., Coen D.M. Identification of a small molecule that inhibits herpes simplex virus DNA Polymerase subunit interactions and viral replication. Chem. Biol. 2004; 11(5): 647-54.Zhou B., Yang K., Wills E., Tang L., Baines J.D. A mutation in the DNA polymerase accessory factor of herpes simplex virus 1 restores viral DNA replication in the presence of raltegravir. J. Virol. 2014; 88(19): 11121-9.Smith R.A., Raugi D.N , Kiviat N.B., Hawes S.E., Mullins J.I., Sow P.S., et al. Phenotypic susceptibility of HIV-2 to raltegravir: integrase mutations Q148R and N155H confer raltegravir resistance. AIDS. 2011; 25(18): 2235-41.Wohl D.A., Dumond J.B., Blevins S., Pittard D., Ragan D., Wang R., et al. Raltegravir pharmacokinetics in treatment-naive patients is not influenced by race: results from the raltegravir early therapy in African-Americans living with HIV (REAL) study. Antimicrob. Agents Chemother. 2013; 57(2): 784-8.