СОВРЕМЕННАЯ ЭТИОТРОПНАЯ ХИМИОТЕРАПИЯ ЦИТОМЕГАЛОВИРУСНОЙ ИНФЕКЦИИ ЧЕЛОВЕКА: КЛИНИЧЕСКАЯ ЭФФЕКТИВНОСТЬ, МОЛЕКУЛЯРНЫЙ МЕХАНИЗМ ДЕЙСТВИЯ, ЛЕКАРСТВЕННАЯ УСТОЙЧИВОСТЬ, НОВЫЕ ТЕНДЕНЦИИ И ПЕРСПЕКТИВЫ. ЧАСТЬ 2

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Ряд синтетических соединений, таких как нуклеозидный аналог ганцикловир, его L-валиновый эфир (представляющий собой метаболический предшественник ганцикловира) и пирофосфатный аналог фоскарнет, разрешены ВОЗ для лечения заболеваний, вызываемых цитомегаловирусом (ЦМВ) человека, в европейском регионе. Биомишенью этих препаратов является вирусная ДНК-полимераза. Однако проведение стандартной анти-ЦМВ-терапии сопровождается тяжёлыми побочными эффектами, а также развитием у вируса лекарственной резистентности, главным образом в условиях иммунодефицита. В этом обзоре мы сконцентрировали внимание на вирусных протеинах, представляющих интерес в качестве новых потенциальных мишеней, и их ингибиторах, таких как ингибитор терминазы ЦМВ человека летермовир, показавший высокую активность в III фазе клинических испытаний, ингибиторы вирусной циклин-зависимой киназы (maribavir, cyclopropavir) и целый ряд соединений, проявляющих анти-ЦМВ-активность, проходящих доклинические испытания в эксперименте. Включение в стандартные профилактические и лечебные схемы новых анти-ЦМВ-агентов, активных против резистентных к ганцикловиру/фоскарнету штаммов ЦМВ, позволит значительно повысить эффективность терапии ЦМВ-инфекции, в том числе в случаях, когда стандартная терапия оказывается неэффективной. Области поиска: международные базы данных MEDLINE, PubMed, eLIBRARY.RU, ClinicalTrials.gov и другие с целью получения информации о соединениях, проявляющих селективное действие в отношении ЦМВ человека, наиболее перспективных для создания лекарственных препаратов.

Об авторах

В. Л. Андронова

ФГБУ «Национальный исследовательский центр эпидемиологии и микробиологии имени почётного академика Н.Ф. Гамалеи» Минздрава России

Автор, ответственный за переписку.
Email: andronova.vl@yandex.ru
Россия

Список литературы

  1. Reeves M., Sinclair J. Aspects of human cytomegalovirus latency and reactivation. Curr. Top. Microbiol. Immunol. 2008; 325: 297-313. PMID: 18637513
  2. Cannon M.J., Schmid D.S., Hyde T.B. Review of cytomegalovirus seroprevalence and de-mographic characteristics associated with infection. Rev. Med. Virol. 2010; 20(4): 202-13. PMID: 20564615 doi: 10.1002/rmv.655
  3. Thorne J.E., Jabs D.A., Kempen J.H., Holbrook J.T., Nichols C., Meinert C.L., et al. Incidence of and risk factors for visual acuity loss among patients with AIDS and cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Ophthalmology. 2006; 113(8): 1432-40. PMID: 16766032 doi: 10.1016/j.ophtha.2006.03.021
  4. Sinzger C., Digel M., Jahn G. Cytomegalovirus cell tropism. Curr. Top. Microbiol. Immunol. 2008; 325: 63-83. PMID: 18637500
  5. Лечение и помощь при ВИЧ/СПИДе. Клинические протоколы для Европейского региона ВОЗ. Available at: http://www.euro.who.int/__data/assets/pdf_file/0018/78111/E90840R.pdf?ua=1
  6. Lanzieri T.M., Dollard S.C., Bialek S.R., Grosse S.D. Systematic review of the birth prevalence of congenital cytomegalovirus infection in developing countries. Int. J. Infect. Dis. 2014; 22: 44-8. PMID: 24631522 PMCID: PMC4829484
  7. Микроцефалия. Информационный бюллетень ВОЗ. Available at: http://www.who.int/mediacentre/factsheets/microcephaly/ru/
  8. Кочкина С.С., Ситникова Е.П. Особенности цитомегаловирусной инфекции: обзор литературы. Доктор.Ру. 2016; (6): 62-7.
  9. Jean Beltran P.M., Cristea I.M. The life cycle and pathogenesis of human cytomegalovirus infection: lessons from proteomics. Expert. Rev. Proteomics. 2014; 11(6): 697-711. PMID: 25327590 PMCID: PMC4604749 doi: 10.1586/14789450.2014.971116
  10. Kalejta R.F. Functions of human cytomegalovirus tegument proteins prior to immediate early gene expression. Curr. Top. Microbiol. Immunol. 2008; 325: 101-15. PMID: 18637502
  11. Stinski M.F., Petrik D.T. Functional roles of the human cytomegalovirus essential IE86 protein. Curr. Top. Microbiol. Immunol. 2008; 325: 133-52. PMID: 18637504
  12. Winkler M., Rice S.A., Stamminger T. UL69 of human cytomegalovirus, an open reading frame with homology to ICP27 of herpes simplex virus, encodes a transactivator of gene expression. J. Virol. 1994; 68(6): 3943-54. PMID: 8189530 PMCID: PMC236900
  13. Alwine J.C. The human cytomegalovirus assembly compartment: a masterpiece of viral manipulation of cellular processes that facilitates assembly and egress. PLoS Pathog. 2012; 8(9): e1002878. PMID: 23028305 PMCID: PMC3447744 doi: 10.1371/journal.ppat.1002878
  14. Das S., Pellett P.E. Spatial relationships between markers for secretory and endosomal machinery in human cytomegalovirus-infected cells versus those in uninfected cells. J. Virol. 2011; 85(12): 5864-79. PMID: 21471245 PMCID: PMC3126327 doi: 10.1128/JVI.00155-11
  15. 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]pyridines as non-nucleoside inhibitors of human cyto-megalovirus and related herpesvirus polymerases. J. Med. Chem. 2005; 48(18): 5794-804. PMID: 16134946 doi: 10.1021/jm050162b
  16. 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. PMID: 12525621 PMCID: PMC140985
  17. Michel D., Mertens T. The UL97 proteinkinase of human cytomegalovirus and homologues in other herpesviruses: impact on virus and host. Biochim. Biophys. Acta. 2004; 1697(1-2): 169-80. PMID: 15023359 doi: 10.1016/j.bbapap.2003.11.022
  18. Smith-Donald B.A., Durand L.O., Roizman B. Role of cellular phosphatase cdc25C in herpes simplex virus 1 replication. J. Virol. 2008; 82(9): 4527-32. PMID: 18272575 PMCID: PMC2293048 doi: 10.1128/JVI.02021-07
  19. Gershburg E., Pagano J.S. Phosphorylation of the Epstein-Barr virus (EBV) DNA polymerase processivity factor EA-D by the EBV-encoded protein kinase and effects of the L-riboside benzimidazole 1263W94. J. Virol. 2002; 76(3): 998-1003. PMID: 11773375 PMCID: PMC135851
  20. Krosky P.M., Baek M.C., Jahng W.J., Barrera I., Harvey R.J., Biron K.K., et al. The human cytomegalovirus UL44 protein is a substrate for the UL97 protein kinase. J. Virol. 2003; 77(14): 7720-7. PMID: 12829811 PMCID: PMC161957
  21. Kawaguchi Y., Matsumura T., Roizman B., Hirai K. Cellular elongation factor 1delta is modified in cells infected with representative alpha-, beta-, or gammaherpesviruses. J. Virol. 1999; 73(5): 4456-60. PMID: 10196346 PMCID: PMC104232
  22. Baek M.C., Krosky P.M., Pearson A., Coen D.M. Phosphorylation of the RNA polymerase II carboxyl-terminal domain in human cytomegalovirus-infected cells and in vitro by the viral UL97 protein kinase. Virology. 2004; 324(1): 184-93. PMID: 15183065 doi: 10.1016/j.virol.2004.03.015
  23. Prichard M.N. Function of human cytomegalovirus UL97 kinase in viral infection and its inhibition by maribavir. Rev. Med. Virol. 2009; 19(4): 215-29. PMID: 19434630 PMCID: PMC3777615 doi: 10.1002/rmv.615
  24. Sharma M., Bender B.J., Kamil J.P., Lye M.F., Pesola J.M, Reim N.I., et al. Human cytomegalovirus UL97 phosphorylates the viral nuclear egress complex. J. Virol. 2015; 89(1): 523-34. PMID: 25339763 PMCID: PMC4301116 doi: 10.1128/JVI.02426-14
  25. Chou S., Ercolani R.J., Marousek G., Bowlin T.L. Cytomegalovirus UL97 kinase catalytic domain mutations that confer multidrug resistance. Antimicrob. Agents Chemother. 2013; 57(7): 3375-9. PMID: 23650173 PMCID: PMC3697320 doi: 10.1128/AAC.00511-13
  26. Chou S. Cytomegalovirus UL97 mutations in the era of ganciclovir and maribavir. Rev. Med. Virol. 2008; 18(4): 233-46. PMID: 18383425 doi: 10.1002/rmv.574
  27. Chou S. Diverse cytomegalovirus UL27 mutations adapt to loss of viral UL97 kinase activity under maribavir. Antimicrob. Agents Chemother. 2009; 53(1): 81-5. PMID: 18981262 PMCID: PMC2612169 doi: 10.1128/AAC.01177-08
  28. Reitsma J.M., Savaryn J.P., Faust K., Sato H., Halligan B.D., Terhune S.S. Antiviral inhibition targeting the HCMV kinase pUL97 requires pUL27-dependent degradation of Tip60 acetyltransferase and cell-cycle arrest. Cell. Host Microbe. 2011; 9(2): 103-14. PMID: 21320693 doi: 10.1016/j.chom.2011.01.006
  29. Prichard M.N., Sztul E., Daily S.L., Perry A.L., Frederick S.L., Gill R.B., et al. Human cytomegalovirus UL97 kinase activity is required for the hyperphosphorylation of retinoblastoma protein and inhibits the formation of nuclear aggresomes. J. Virol. 2008; 82(10): 5054-67. PMID: 18321963 PMCID: PMC2346732 doi: 10.1128/JVI.02174 07
  30. Purves F.C., Roizman B. The UL13 gene of herpes simplex virus 1 encodes the functions for posttranslational processing associated with phosphorylation of the regulatory protein alpha 22. Proc. Natl. Acad. Sci. USA. 1992; 89(16): 7310-4. PMID: 1323829 PMCID: PMC49699
  31. Lalezari J.P., Aberg J.A., Wang L.H., Wire M.B., Miner R., Snowden W., et al. Phase I do-se escalation trial evaluating the pharmacokinetics, anti-human cytomegalovirus (HCMV) activity, and safety of 1263W94 in human immunodeficiency virus-infected men with asymptomatic HCMV shedding. Antimicrob. Agents Chemother. 2002; 46(9): 2969-76. PMID: 12183255 PMCID: PMC127448
  32. Ma J.D., Nafziger A.N., Villano S.A., Gaedigk A., Bertino J.S., Maribavir pharmacokinetics and the effects of multiple-dose maribavir on cytochrome P450 (CYP) 1A2, CYP 2C9, CYP 2C19, CYP 2D6, CYP 3A, N-acetyltransferase-2, and xanthine oxidase activities in healthy adults. Antimicrob. Agents Chemother. 2006; 50(4): 1130-5. PMID: 16569820 PMCID: PMC1426970 doi: 10.1128/AAC.50.4.1130-1135.2006
  33. Marty F.M., Ljungman P., Papanicolaou G.A., Winston D.J., Chemaly R.F., Strasfeld L., et al. Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: a phase 3, double-blind, placebo-controlled, randomized trial. Lancet Infect. Dis. 2011; 11(4): 284-92. PMID: 21414843 doi: 10.1016/S1473-3099(11)70024-X
  34. Winston D.J., Saliba F., Blumberg E., Abouljoud M., Garcia-Diaz J.B., Goss J.A., et al. Efficacy and safety of maribavir dosed at 100 mg orally twice daily for the prevention of cytomegalovirus disease in liver transplant recipients: a randomized, double-blind, multicenter controlled trial. Am. J. Transplant. 2012; 12(11): 3021-30. PMID: 22947426 doi: 10.1111/j.1600-6143.2012.04231.x
  35. Alain S., Revest M., Veyer D., Essig M., Rerolles J.P., Rawlinson W., et al. Maribavir use in practice for cytomegalovirus infection in French transplantation centers. Transplant. Proc. 2013; 45(4): 1603-7. PMID: 23726629 doi: 10.1016/j.transproceed.2013.01.082
  36. Schubert A., Ehlert K., Schuler-Luettmann S., Gentner E., Mertens T., Michel D. Fast selection of maribavir resistant cytomegalovirus in a bone marrow transplant recipient. BMC Infect. Dis. 2013; 13: 330. PMID: 23870704 PMCID: PMC3720178 doi: 10.1186/1471-2334-13-330
  37. Evers D.L., Komazin G., Shin D., Hwang D.D., Townsend L.B., Drach J.C. Interactions among antiviral drugs acting late in the replication cycle of human cytomegalovirus. Antiviral. Res. 2002; 56(1): 61-72. PMID: 12323400
  38. Kern E.R., Kushner N.L., Hartline C.B., Williams-Aziz S.L., Harden E.A., Zhou S., et al. Invitro activity and mechanism of action of methylenecyclopropane analogs of nucleosides against herpesvirus replication. Antimicrob. Agents Chemother. 2005; 49(3): 1039-45. PMID: 15728900 PMCID: PMC549243 doi: 10.1128/AAC.49.3.1039-1045.2005
  39. Kern E.R., Bidanset D.J., Hartline C.B., Yan Z., Zemlicka J., Quenelle D.C. Oral activity of a methylenecyclopropane analog, cyclopropavir, in animal models for cytomegalovirus infections. Antimicrob. Agents Chemother. 2004; 48(12): 4745-53. PMID: 15561852 PMCID: PMC529216 doi: 10.1128/AAC.48.12.4745-4753.2004
  40. Gentry B.G., Gentry S.N., Jackson T.L., Zemlicka J., Drach J.C. Phosphorylation of antiviral and endogenous nucleotides to di- and triphosphates by guanosine monophosphate kinase. Biochem. Pharmacol. 2011; 819(1): 43-9. PMID: 20846508 doi: 10.1016/j.bcp.2010.09.005
  41. Hakki M., Drummond C., Houser B., Marousek G., Chou S. Resistance to maribavir is associated with the exclusion of pUL27 from nucleoli during human cytomegalovirus infection. Antiviral. Res. 2011; 92(2): 313-8. PMID: 21906628 PMCID: PMC3232008 doi: 10.1016/j.antiviral.2011.08.019
  42. Chou S., Komazin-Meredith G., Williams J.D., Bowlin T.L. Cytomegalovirus mutants resistant to ganciclovir and cidofovir differ in susceptibilities to synguanol and its 6-ether and 6-thioether derivatives. Antimicrob. Agents Chemother. 2014; 58(3): 1809-12. PMID: 24379208 PMCID: PMC3957852 doi: 10.1128/AAC.02544-13
  43. Song Y.J., Stinski M.F. Effect of the human cytomegalovirus IE86 protein on expression of E2F-responsive genes: a DNA microarray analysis. Proc. Natl. Acad. Sci. USA. 2002; 99(5): 2836-41. doi: 10.1073/pnas.052010099; PMID: 11867723; PMCID PMC122434
  44. Loregian A., Mercorelli B., Muratore G., Sinigalia E., Pagni S., Massari S., et al. The 6-aminoquinolone WC5 inhibits human cytomegalovirus replication at an early stage by interfering with the transactivating activity of viral immediate-early 2 protein. Antimicrob. Agents Chemother. 2010; 54(5): 1930-40. PMID: 20194695 PMCID: PMC2863603 doi: 10.1128/AAC.01730-09.
  45. Massari S., Mercorelli B., Sancineto L., Sabatini S., Cecchetti V., Gribaudo G., et al. Design, synthesis, and evaluation of WC5 analogues as inhibitors of human cytomegalovirus Immediate-Early 2 protein, a promising target for anti-HCMV treatment. Chem. Med. Chem. 2013; 8(8): 1403-14. PMID: 23757191 doi: 10.1002/cmdc.201300106
  46. Mercorelli B., Luganini A., Muratore G., Massari S., Terlizzi M.E., Tabarrini O., et al. The 6-Aminoquinolone WC5 inhibits different functions of the immediate-early 2 (IE2) protein of human cytomegalovirus that are essential for viral replication. Antimicrob. Agents Chemother. 2014; 58(11): 6615-26. doi: 10.1128/AAC.03309-14. PMID: 25155603 PMCID: PMC4249379
  47. Tandon R., Mocarski E.S. Viral and host control of cytomegalovirus maturation. Trends Microbiol. 2012; 20(8): 392-401. PMID: 22633075 PMCID: PMC3408842 doi: 10.1016/j.tim.2012.04.008
  48. Neuber S., Wagner K., Goldner T., Lischka P., Steinbrueck L., Messerle M., et al. Mutual interplay between the cytomegalovirus terminase subunits pUL51, pUL56 and pUL89 promotes terminase complex formation. J. Virol. 2017; 91(12): e02384-16. PMID: 28356534 PMCID: PMC5446633 doi: 10.1128/JVI.02384-16
  49. Marschall M., Stamminger T., Urban A., Wildum S., Ruebsamen-Schaeff H., Zimmermann H., et al. In Vitro Evaluation of the Activities of the Novel Anticytomegalovirus Compound AIC246 (Letermovir) against Herpesviruses and Other Human Pathogenic Viruses. Antimicrob. Agents Chemother. 2012; 56(2): 1135-7. PMID: 22106211 PMCID: PMC3264222 doi: 10.1128/AAC.05908-11
  50. Goldner T., Hewlett G., Ettischer N., Ruebsamen-Schaeff H., Zimmermann H., Lischka P. The Novel Anticytomegalovirus Compound AIC246 (Letermovir) Inhibits Human Cytomegalovirus Replication through a Specific Antiviral Mechanism That Involves the Viral Terminase. J. Virol. 2011; 85(20): 10884-93. PMID: 21752907 PMCID: PMC3187482 doi: 10.1128/JVI.05265-11
  51. Goldner T., Zimmermann H., Lischka P. Phenotypic characterization of two naturally occurring human Cytomegalovirus sequence polymorphisms located in a distinct region of ORF UL56 known to be involved in in vitro resistance to letermovir. Antiviral. Res. 2015; 116: 48-50. PMID: 25637709 doi: 10.1016/j.antiviral.2015.01.006
  52. Kaul D.R., Stoelben S., Cober E., Ojo T., Sandusky E., Lischka P., et al. First repor to successful treatment of multidrug-resistant cytomegalovirus disease with the novel anti-CMV compound AIC246. Am. J. Transplant. 2011; 11(5): 1079-84. PMID: 21521474 doi: 10.1111/j.1600-6143.2011.03530.x
  53. Stoelben S., Arns W., Renders L., Hummel J., Mühlfeld A., Stangl M., et al. Preemptive treatment of Cytomegalovirus infection in kidney transplant recipients with letermovir: results of a Phase 2a study. Transpl. Int. 2014; 27(1): 77-86. PMID: 24164420 doi: 10.1111/tri.12225
  54. Chemaly R.F., Ullmann A.J., Stoelben S., Richard M.P., Bornhäuser M., Groth C., et al. Letermovir for Cytomegalovirus Prophylaxis in Hematopoietic-Cell Transplantation. N. Engl. J. Med. 2014; 370(19): 1781-9. PMID: 24806159 doi: 10.1056/NEJMoa1309533
  55. Lischka P., Michel D., Zimmermann H. Characterization of Cytomegalovirus Breakthrough Events in a Phase 2 Prophylaxis Trial of Letermovir (AIC246, MK 8228). J. Infect. Dis. 2016; 213(1): 23-30. PMID: 26113373 doi: 10.1093/infdis/jiv352
  56. Merck’s Letermovir, an investigational antiviral medicine for prevention of cytomegalovirus (CMV) infection in bone marrow transplant recipients, highly effective though week 24 post-transplant in pivotal phase 3 study. Available at: http://www.mrknewsroom.com/news-release/research-and-development-news/mercks-letermovir-investigational-antiviral-medicine-prev
  57. McSharry J.J., McDonough A., Olson B., Hallenberger S., Reefschlaeger J., Bender W., et al. Susceptibilities of human cytomegalovirus clinical isolates to BAY38-4766, BAY43-9695, and ganciclovir. Antimicrob. Agents Chemother. 2001; 45(10): 2925-7. PMID: 11557492 PMCID: PMC90754 doi: 10.1128/AAC.45.10.2925-2927.2001
  58. Reefschlaeger J., Bender W., Hallenberger S., Weber O., Eckenberg P., Goldmann S., et al. Novel non-nucleoside inhibitors of cytomegaloviruses (BAY 38-4766): in vitro and in vivo antiviral activity and mechanism of action. J. Antimicrob. Chemother. 2001; 48(6): 757-67. PMID: 11733458
  59. Manicklal S., Emery V.C., Lazzarotto T., Boppana S.B., Gupta R.K. The “silent” global burden of congenital cytomegalovirus. Clin. Microbiol. Rev. 2013; 26(1): 86-102. PMID: 23297260 PMCID: PMC3553672 doi: 10.1128/CMR.00062-12
  60. Morère L., Andouard D., Labrousse F., Saade F., Calliste C.A., Cotin S., et al. Ex vivo model of congenital cytomegalovirus infection and new combination therapies. Placenta. 2015; 36(1): 41-7. PMID: 25479789 doi: 10.1016/j.placenta.2014.11.003
  61. Reeves M., Sinclair J. Aspects of human cytomegalovirus latency and reactivation. Curr. Top. Microbiol. Immunol. 2008; 325: 297-313. PMID: 18637513
  62. Cannon M.J., Schmid D.S., Hyde T.B. Review of cytomegalovirus seroprevalence and de-mographic characteristics associated with infection. Rev. Med. Virol. 2010; 20(4): 202-13. PMID: 20564615 doi: 10.1002/rmv.655
  63. Thorne J.E., Jabs D.A., Kempen J.H., Holbrook J.T., Nichols C., Meinert C.L., et al. Incidence of and risk factors for visual acuity loss among patients with AIDS and cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Ophthalmology. 2006; 113(8): 1432-40. PMID: 16766032 doi: 10.1016/j.ophtha.2006.03.021
  64. Sinzger C., Digel M., Jahn G. Cytomegalovirus cell tropism. Curr. Top. Microbiol. Immunol. 2008; 325: 63-83. PMID: 18637500
  65. HIV/AIDS treatment and care. Clinical protocols for the WHO European Region. Available at: http://www.euro.who.int/__data/assets/pdf_file/0004/78106/E90840.pdf?ua=1
  66. Lanzieri T.M., Dollard S.C., Bialek S.R., Grosse S.D. Systematic review of the birth prevalence of congenital cytomegalovirus infection in developing countries. Int. J. Infect. Dis. 2014; 22: 44-8. PMID: 24631522 PMCID: PMC4829484 doi: 10.1016/j.ijid.2013.12.010
  67. Microcephaly. Fact sheet of WHO. Available at: http://www.who.int/news-room/fact-sheets/detail/microcephaly
  68. Kochkina S.S., Sitnikova E.P Specific features of cytomegalovirus infection: literature review. Doktor.Ru. 2016; (6): 62-7. (in Russian)
  69. Jean Beltran P.M., Cristea I.M. The life cycle and pathogenesis of human cytomegalovirus infection: lessons from proteomics. Expert. Rev. Proteomics. 2014; 11(6): 697-711. PMID: 25327590 PMCID: PMC4604749 doi: 10.1586/14789450.2014.971116
  70. Kalejta R.F. Functions of human cytomegalovirus tegument proteins prior to immediate early gene expression. Curr. Top. Microbiol. Immunol. 2008; 325: 101-15. PMID: 18637502
  71. Stinski M.F., Petrik D.T. Functional roles of the human cytomegalovirus essential IE86 protein. Curr. Top. Microbiol. Immunol. 2008; 325: 133-52. PMID: 18637504
  72. Winkler M., Rice S.A., Stamminger T. UL69 of human cytomegalovirus, an open reading frame with homology to ICP27 of herpes simplex virus, encodes a transactivator of gene expression. J. Virol. 1994; 68(6): 3943-54. PMID: 8189530 PMCID: PMC236900
  73. Alwine J.C. The human cytomegalovirus assembly compartment: a masterpiece of viral manipulation of cellular processes that facilitates assembly and egress. PLoS Pathog. 2012; 8(9): e1002878. PMID: 23028305 PMCID: PMC3447744 doi: 10.1371/journal.ppat.1002878
  74. Das S., Pellett P.E. Spatial relationships between markers for secretory and endosomal machinery in human cytomegalovirus-infected cells versus those in uninfected cells. J. Virol. 2011; 85(12): 5864-79. PMID: 21471245 PMCID: PMC3126327 doi: 10.1128/JVI.00155-11
  75. 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]pyridines as non-nucleoside inhibitors of human cyto-megalovirus and related herpesvirus polymerases. J. Med. Chem. 2005; 48(18): 5794-804. PMID: 16134946 doi: 10.1021/jm050162b
  76. 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. PMID: 12525621 PMCID: PMC140985
  77. Michel D., Mertens T. The UL97 proteinkinase of human cytomegalovirus and homologues in other herpesviruses: impact on virus and host. Biochim. Biophys. Acta. 2004; 1697(1-2): 169-80. PMID: 15023359 doi: 10.1016/j.bbapap.2003.11.022
  78. Smith-Donald B.A., Durand L.O., Roizman B. Role of cellular phosphatase cdc25C in herpes simplex virus 1 replication. J. Virol. 2008; 82(9): 4527-32. PMID: 18272575 PMCID: PMC2293048 doi: 10.1128/JVI.02021-07
  79. Gershburg E., Pagano J.S. Phosphorylation of the Epstein-Barr virus (EBV) DNA polymerase processivity factor EA-D by the EBV-encoded protein kinase and effects of the L-riboside benzimidazole 1263W94. J. Virol. 2002; 76(3): 998-1003. PMID: 11773375 PMCID: PMC135851
  80. Krosky P.M., Baek M.C., Jahng W.J., Barrera I., Harvey R.J., Biron K.K., et al. The human cytomegalovirus UL44 protein is a substrate for the UL97 protein kinase. J. Virol. 2003; 77(14): 7720-7. PMID: 12829811 PMCID: PMC161957
  81. Kawaguchi Y., Matsumura T., Roizman B., Hirai K. Cellular elongation factor 1delta is modified in cells infected with representative alpha-, beta-, or gammaherpesviruses. J. Virol. 1999; 73(5): 4456-60. PMID: 10196346 PMCID: PMC104232
  82. Baek M.C., Krosky P.M., Pearson A., Coen D.M. Phosphorylation of the RNA polymerase II carboxyl-terminal domain in human cytomegalovirus-infected cells and in vitro by the viral UL97 protein kinase. Virology. 2004; 324(1): 184-93. PMID: 15183065 doi: 10.1016/j.virol.2004.03.015
  83. Prichard M.N. Function of human cytomegalovirus UL97 kinase in viral infection and its inhibition by maribavir. Rev. Med. Virol. 2009; 19(4): 215-29. PMID: 19434630 PMCID: PMC3777615 doi: 10.1002/rmv.615
  84. Sharma M., Bender B.J., Kamil J.P., Lye M.F., Pesola J.M, Reim N.I., et al. Human cytomegalovirus UL97 phosphorylates the viral nuclear egress complex. J. Virol. 2015; 89(1): 523-34. PMID: 25339763 PMCID: PMC4301116 doi: 10.1128/JVI.02426-14
  85. Chou S., Ercolani R.J., Marousek G., Bowlin T.L. Cytomegalovirus UL97 kinase catalytic domain mutations that confer multidrug resistance. Antimicrob. Agents Chemother. 2013; 57(7): 3375-9. PMID: 23650173 PMCID: PMC3697320 doi: 10.1128/AAC.00511-13
  86. Chou S. Cytomegalovirus UL97 mutations in the era of ganciclovir and maribavir. Rev. Med. Virol. 2008; 18(4): 233-46. PMID: 18383425 doi: 10.1002/rmv.574
  87. Chou S. Diverse cytomegalovirus UL27 mutations adapt to loss of viral UL97 kinase activity under maribavir. Antimicrob. Agents Chemother. 2009; 53(1): 81-5. PMID: 18981262 PMCID: PMC2612169 doi: 10.1128/AAC.01177-08
  88. Reitsma J.M., Savaryn J.P., Faust K., Sato H., Halligan B.D., Terhune S.S. Antiviral inhibition targeting the HCMV kinase pUL97 requires pUL27-dependent degradation of Tip60 acetyltransferase and cell-cycle arrest. Cell. Host Microbe. 2011; 9(2): 103-14. PMID: 21320693 doi: 10.1016/j.chom.2011.01.006
  89. Prichard M.N., Sztul E., Daily S.L., Perry A.L., Frederick S.L., Gill R.B., et al. Human cytomegalovirus UL97 kinase activity is required for the hyperphosphorylation of retinoblastoma protein and inhibits the formation of nuclear aggresomes. J. Virol. 2008; 82(10): 5054-67. PMID: 18321963 PMCID: PMC2346732 doi: 10.1128/JVI.02174 07
  90. Purves F.C., Roizman B. The UL13 gene of herpes simplex virus 1 encodes the functions for posttranslational processing associated with phosphorylation of the regulatory protein alpha 22. Proc. Natl. Acad. Sci. USA. 1992; 89(16): 7310-4. PMID: 1323829 PMCID: PMC49699
  91. Lalezari J.P., Aberg J.A., Wang L.H., Wire M.B., Miner R., Snowden W., et al. Phase I do-se escalation trial evaluating the pharmacokinetics, anti-human cytomegalovirus (HCMV) activity, and safety of 1263W94 in human immunodeficiency virus-infected men with asymptomatic HCMV shedding. Antimicrob. Agents Chemother. 2002; 46(9): 2969-76. PMID: 12183255 PMCID: PMC127448
  92. Ma J.D., Nafziger A.N., Villano S.A., Gaedigk A., Bertino J.S., Maribavir pharmacokinetics and the effects of multiple-dose maribavir on cytochrome P450 (CYP) 1A2, CYP 2C9, CYP 2C19, CYP 2D6, CYP 3A, N-acetyltransferase-2, and xanthine oxidase activities in healthy adults. Antimicrob. Agents Chemother. 2006; 50(4): 1130-5. PMID: 16569820 PMCID: PMC1426970 doi: 10.1128/AAC.50.4.1130-1135.2006
  93. Marty F.M., Ljungman P., Papanicolaou G.A., Winston D.J., Chemaly R.F., Strasfeld L., et al. Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: a phase 3, double-blind, placebo-controlled, randomized trial. Lancet Infect. Dis. 2011; 11(4): 284-92. PMID: 21414843 doi: 10.1016/S1473-3099(11)70024-X
  94. Winston D.J., Saliba F., Blumberg E., Abouljoud M., Garcia-Diaz J.B., Goss J.A., et al. Efficacy and safety of maribavir dosed at 100 mg orally twice daily for the prevention of cytomegalovirus disease in liver transplant recipients: a randomized, double-blind, multicenter controlled trial. Am. J. Transplant. 2012; 12(11): 3021-30. PMID: 22947426 doi: 10.1111/j.1600-6143.2012.04231.x
  95. Alain S., Revest M., Veyer D., Essig M., Rerolles J.P., Rawlinson W., et al. Maribavir use in practice for cytomegalovirus infection in French transplantation centers. Transplant. Proc. 2013; 45(4): 1603-7. PMID: 23726629 doi: 10.1016/j.transproceed.2013.01.082
  96. Schubert A., Ehlert K., Schuler-Luettmann S., Gentner E., Mertens T., Michel D. Fast selection of maribavir resistant cytomegalovirus in a bone marrow transplant recipient. BMC Infect. Dis. 2013; 13: 330. PMID: 23870704 PMCID: PMC3720178 doi: 10.1186/1471-2334-13-330
  97. Evers D.L., Komazin G., Shin D., Hwang D.D., Townsend L.B., Drach J.C. Interactions among antiviral drugs acting late in the replication cycle of human cytomegalovirus. Antiviral. Res. 2002; 56(1): 61-72. PMID: 12323400
  98. Kern E.R., Kushner N.L., Hartline C.B., Williams-Aziz S.L., Harden E.A., Zhou S., et al. Invitro activity and mechanism of action of methylenecyclopropane analogs of nucleosides against herpesvirus replication. Antimicrob. Agents Chemother. 2005; 49(3): 1039-45. PMID: 15728900 PMCID: PMC549243 doi: 10.1128/AAC.49.3.1039-1045.2005
  99. Kern E.R., Bidanset D.J., Hartline C.B., Yan Z., Zemlicka J., Quenelle D.C. Oral activity of a methylenecyclopropane analog, cyclopropavir, in animal models for cytomegalovirus infections. Antimicrob. Agents Chemother. 2004; 48(12): 4745-53. PMID: 15561852 PMCID: PMC529216 doi: 10.1128/AAC.48.12.4745-4753.2004
  100. Gentry B.G., Gentry S.N., Jackson T.L., Zemlicka J., Drach J.C. Phosphorylation of antiviral and endogenous nucleotides to di- and triphosphates by guanosine monophosphate kinase. Biochem. Pharmacol. 2011; 819(1): 43-9. PMID: 20846508 doi: 10.1016/j.bcp.2010.09.005
  101. Hakki M., Drummond C., Houser B., Marousek G., Chou S. Resistance to maribavir is associated with the exclusion of pUL27 from nucleoli during human cytomegalovirus infection. Antiviral. Res. 2011; 92(2): 313-8. PMID: 21906628 PMCID: PMC3232008 doi: 10.1016/j.antiviral.2011.08.019
  102. Chou S., Komazin-Meredith G., Williams J.D., Bowlin T.L. Cytomegalovirus mutants resistant to ganciclovir and cidofovir differ in susceptibilities to synguanol and its 6-ether and 6-thioether derivatives. Antimicrob. Agents Chemother. 2014; 58(3): 1809-12. PMID: 24379208 PMCID: PMC3957852 doi: 10.1128/AAC.02544-13
  103. Song Y.J., Stinski M.F. Effect of the human cytomegalovirus IE86 protein on expression of E2F-responsive genes: a DNA microarray analysis. Proc. Natl. Acad. Sci. USA. 2002; 99(5): 2836-41. doi: 10.1073/pnas.052010099; PMID: 11867723; PMCID PMC122434
  104. Loregian A., Mercorelli B., Muratore G., Sinigalia E., Pagni S., Massari S., et al. The 6-aminoquinolone WC5 inhibits human cytomegalovirus replication at an early stage by interfering with the transactivating activity of viral immediate-early 2 protein. Antimicrob. Agents Chemother. 2010; 54(5): 1930-40. PMID: 20194695 PMCID: PMC2863603 doi: 10.1128/AAC.01730-09.
  105. Massari S., Mercorelli B., Sancineto L., Sabatini S., Cecchetti V., Gribaudo G., et al. Design, synthesis, and evaluation of WC5 analogues as inhibitors of human cytomegalovirus Immediate-Early 2 protein, a promising target for anti-HCMV treatment. Chem. Med. Chem. 2013; 8(8): 1403-14. PMID: 23757191 doi: 10.1002/cmdc.201300106
  106. Mercorelli B., Luganini A., Muratore G., Massari S., Terlizzi M.E., Tabarrini O., et al. The 6-Aminoquinolone WC5 inhibits different functions of the immediate-early 2 (IE2) protein of human cytomegalovirus that are essential for viral replication. Antimicrob. Agents Chemother. 2014; 58(11): 6615-26. doi: 10.1128/AAC.03309-14. PMID: 25155603 PMCID: PMC4249379
  107. Tandon R., Mocarski E.S. Viral and host control of cytomegalovirus maturation. Trends Microbiol. 2012; 20(8): 392-401. PMID: 22633075 PMCID: PMC3408842 doi: 10.1016/j.tim.2012.04.008
  108. Neuber S., Wagner K., Goldner T., Lischka P., Steinbrueck L., Messerle M., et al. Mutual interplay between the cytomegalovirus terminase subunits pUL51, pUL56 and pUL89 promotes terminase complex formation. J. Virol. 2017; 91(12): e02384-16. PMID: 28356534 PMCID: PMC5446633 doi: 10.1128/JVI.02384-16
  109. Marschall M., Stamminger T., Urban A., Wildum S., Ruebsamen-Schaeff H., Zimmermann H., et al. In Vitro Evaluation of the Activities of the Novel Anticytomegalovirus Compound AIC246 (Letermovir) against Herpesviruses and Other Human Pathogenic Viruses. Antimicrob. Agents Chemother. 2012; 56(2): 1135-7. PMID: 22106211 PMCID: PMC3264222 doi: 10.1128/AAC.05908-11
  110. Goldner T., Hewlett G., Ettischer N., Ruebsamen-Schaeff H., Zimmermann H., Lischka P. The Novel Anticytomegalovirus Compound AIC246 (Letermovir) Inhibits Human Cytomegalovirus Replication through a Specific Antiviral Mechanism That Involves the Viral Terminase. J. Virol. 2011; 85(20): 10884-93. PMID: 21752907 PMCID: PMC3187482 doi: 10.1128/JVI.05265-11
  111. Goldner T., Zimmermann H., Lischka P. Phenotypic characterization of two naturally occurring human Cytomegalovirus sequence polymorphisms located in a distinct region of ORF UL56 known to be involved in in vitro resistance to letermovir. Antiviral. Res. 2015; 116: 48-50. PMID: 25637709 doi: 10.1016/j.antiviral.2015.01.006
  112. Kaul D.R., Stoelben S., Cober E., Ojo T., Sandusky E., Lischka P., et al. First repor to successful treatment of multidrug-resistant cytomegalovirus disease with the novel anti-CMV compound AIC246. Am. J. Transplant. 2011; 11(5): 1079-84. PMID: 21521474 doi: 10.1111/j.1600-6143.2011.03530.x
  113. Stoelben S., Arns W., Renders L., Hummel J., Mühlfeld A., Stangl M., et al. Preemptive treatment of Cytomegalovirus infection in kidney transplant recipients with letermovir: results of a Phase 2a study. Transpl. Int. 2014; 27(1): 77-86. PMID: 24164420 doi: 10.1111/tri.12225
  114. Chemaly R.F., Ullmann A.J., Stoelben S., Richard M.P., Bornhäuser M., Groth C., et al. Letermovir for Cytomegalovirus Prophylaxis in Hematopoietic-Cell Transplantation. N. Engl. J. Med. 2014; 370(19): 1781-9. PMID: 24806159 doi: 10.1056/NEJMoa1309533
  115. Lischka P., Michel D., Zimmermann H. Characterization of Cytomegalovirus Breakthrough Events in a Phase 2 Prophylaxis Trial of Letermovir (AIC246, MK 8228). J. Infect. Dis. 2016; 213(1): 23-30. PMID: 26113373 doi: 10.1093/infdis/jiv352
  116. Merck’s Letermovir, an investigational antiviral medicine for prevention of cytomegalovirus (CMV) infection in bone marrow transplant recipients, highly effective though week 24 post-transplant in pivotal phase 3 study. Available at: http://www.mrknewsroom.com/news-release/research-and-development-news/mercks-letermovir-investigational-antiviral-medicine-prev
  117. McSharry J.J., McDonough A., Olson B., Hallenberger S., Reefschlaeger J., Bender W., et al. Susceptibilities of human cytomegalovirus clinical isolates to BAY38-4766, BAY43-9695, and ganciclovir. Antimicrob. Agents Chemother. 2001; 45(10): 2925-7. PMID: 11557492 PMCID: PMC90754 doi: 10.1128/AAC.45.10.2925-2927.2001
  118. Reefschlaeger J., Bender W., Hallenberger S., Weber O., Eckenberg P., Goldmann S., et al. Novel non-nucleoside inhibitors of cytomegaloviruses (BAY 38-4766): in vitro and in vivo antiviral activity and mechanism of action. J. Antimicrob. Chemother. 2001; 48(6): 757-67. PMID: 11733458
  119. Manicklal S., Emery V.C., Lazzarotto T., Boppana S.B., Gupta R.K. The “silent” global burden of congenital cytomegalovirus. Clin. Microbiol. Rev. 2013; 26(1): 86-102. PMID: 23297260 PMCID: PMC3553672 doi: 10.1128/CMR.00062-12
  120. Morère L., Andouard D., Labrousse F., Saade F., Calliste C.A., Cotin S., et al. Ex vivo model of congenital cytomegalovirus infection and new combination therapies. Placenta. 2015; 36(1): 41-7.

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