Novel inhibitors of human CMV

Current Opinion in Investigational Drugs

Volumn 9, Issue 2, 2008, Pages 132-145

  Andrei, G ^a   De Clercq, E ^a   Snoeck, R ^a  

^a REGA INSTITUTE FOR MEDICAL RESEARCH   (Belgium)

Author keywords

Cellular targets; Human CMV; Non nucleoside inhibitors; Nucleotide inhibitors

Indexed keywords

1 BENZYLOXYCARBONYLAZETIDINE; BENZIMIDAVIR; BENZIMIDAZOLE; CIDOFOVIR; CORTICOSTEROID; CYCLOOXYGENASE 2 INHIBITOR; FLAVOPIRIDOL; FOMIVIRSEN; FOSCARNET SODIUM; GANCICLOVIR; OLOMOUCINE; PNU 181128; PNU 181465; PNU 183792; PNU 26370; PROTEASOME INHIBITOR; PROTEINASE INHIBITOR; PYRROLIDINE 5,5 LACTAM; ROSCOVITINE; SMALL INTERFERING RNA; UNCLASSIFIED DRUG; VALGANCICLOVIR;

BIOAVAILABILITY; CLINICAL TRIAL; CYTOMEGALOVIRUS INFECTION; DRUG EFFICACY; DRUG MECHANISM; DRUG RESISTANCE; DRUG STRUCTURE; GENE EXPRESSION; HIGHLY ACTIVE ANTIRETROVIRAL THERAPY; HUMAN; IMMUNOCOMPROMISED PATIENT; MORTALITY; PROPHYLAXIS; PROTEIN PROTEIN INTERACTION; RETINITIS; REVIEW; VIRUS GENE;

ANIMALS; ANTIVIRAL AGENTS; CYTOMEGALOVIRUS; CYTOMEGALOVIRUS INFECTIONS; HUMANS; MOLECULAR STRUCTURE; VIRUS ASSEMBLY; VIRUS ATTACHMENT; VIRUS INTERNALIZATION; VIRUS REPLICATION;

EID: 38849196302     PISSN: 14724472     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (141)

1. Gandhi MK, Khanna R: Human cytomegalovirus: Clinical aspects, immune regulation, and emerging treatments. Lancet Infect Dis (2004) 4(12):725-738. • A detailed review of CMV pathogenesis and immune regulation.
2. Palella FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, Holmberg SD: Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med (1998) 338(13):853-860.
3. Forrest DM, Seminari E, Hogg RS, Yip B, Raboud J, Lawson L, Phillips P, Schechter MT, O'Shaughnessy MV, Montaner JS: The incidence and spectrum of AIDS-defining illnesses in persons treated with antiretroviral drugs. Clin Infect Dis (1998) 27(6):1379-1385.
4. Deayton JR, Sabin CA, Johnson MA, Emery VC, Wilson P, Griffiths PD: Importance of cytomegalovirus viraemia in risk of disease progression and death in HIV-infected patients receiving highly active antiretroviral therapy. Lancet (2004) 363(9427):2116-2121.
5. Griffiths PD, Clark DA, Emery VC: Betaherpesviruses in transplant recipients. J Antimicrob Chemother (2000) 45(Suppl 1):29-34.
6. Ljungman P: Beta-herpesvirus challenges in the transplant recipient. J Infect Dis (2002) 186(Suppl 1):S99-S109.
7. Cope AV, Sweny P, Sabin C, Rees L, Griffiths PD, Emery VC: Quantity of cytomegalovirus viruria is a major risk factor for cytomegalovirus disease after renal transplantation. J Med Virol (1997) 52(2):200-205.
8. Razonable RR, Emery VC: Management of CMV infection and disease in transplant patients. Herpes (2004) 11(3):77-86.
9. Singh N: Cytomegalovirus infection in solid organ transplant recipients: New challenges and their implications for preventive strategies. J Clin Virol (2006) 35(4):474-477.
10. Hassan-Walker AF, Kidd IM, Sabin C, Sweny P, Griffiths PD, Emery VC: Quantity of human cytomegalovirus (CMV) DNAemia as a risk factor for CMV disease in renal allograft recipients: Relationship with donor/recipient CMV serostatus, receipt of augmented methylprednisolone and antithymocyte globulin (ATG). J Med Virol (1999) 58(2):182-187.
11. Gandhi MK, Wills MR, Sissons JG, Carmichael AJ: Human cytomegalovirus-specific immunity following haemopoietic stem cell transplantation. Blood Rev (2003) 17(4):259-264.
12. Boeckh M, Nichols WG: The impact of cytomegalovirus serostatus of donor and recipient before hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy. Blood (2004) 103(6):2003-2008.
13. Ljungman P, Perez-Bercoff L, Jonsson J, Avetisyan G, Sparrelid E, Aschan J, Barkholt L, Larsson K, Winiarski J, Yun Z, Ringdén O: Risk factors for the development of cytomegalovirus disease after allogeneic stem cell transplantation. Haematologica (2006) 91(1):78-83.
14. Singh N, Wagener MM: Strategies to prevent organ disease by cytomegalovirus in solid organ transplant recipients. Ann Intern Med (2006) 144(6):456-457.
15. Boeckh M, Leisenring W, Riddell SR, Bowden RA, Huang ML, Myerson D, Stevens-Ayers T, Flowers ME, Cunningham T, Corey L: Late cytomegalovirus disease and mortality in recipients of allogeneic hematopoietic stem cell transplants: Importance of viral load and T-cell immunity. Blood (2003) 101(2):407-414.
16. Goodrich JM, Bowden RA, Fisher L, Keller C, Schoch G, Meyers JD: Ganciclovir prophylaxis to prevent cytomegalovirus disease after allogeneic marrow transplant. Ann Intern Med (1993) 118(3):173-178.
17. Li CR, Greenberg PD, Gilbert MJ, Goodrich JM, Riddell SR: Recovery of HLA-restricted cytomegalovirus (CMV)-specific T-cell responses after allogeneic bone marrow transplant: Correlation with CMV disease and effect of ganciclovir prophylaxis. Blood (1994) 83(7):1971-1979.
18. Whitley RJ: Congenital cytomegalovirus infection: Epidemiology and treatment. Adv Exp Med Biol (2004) 549:155-160.
19. Hassan J, Connell J: Translational mini-review series on infectious disease: Congenital cytomegalovirus infection: 50 Years on. Clin Exp Immunol (2007) 149(2):205-210.
20. Stagno S, Pass RF, Cloud G, Britt WJ, Henderson RE, Walton PD, Veren DA, Page F, Alford CA: Primary cytomegalovirus infection in pregnancy. Incidence, transmission to fetus, and clinical outcome. J Am Med Assoc (1986) 256(14):1904-1908.
21. Alford CA, Stagno S, Pass RF, Britt WJ: Congenital and perinatal cytomegalovirus infections. Rev Infect Dis (1990) 12(Suppl 7):S745-S753.
22. Boppana SB, Pass RF, Britt WJ, Stagno S, Alford CA: Symptomatic congenital cytomegalovirus infection: Neonatal morbidity and mortality. Pediatr Infect Dis J (1992) 11(2):93-99.
23. Boppana SB, Fowler KB, Britt WJ, Stagno S, Pass RF: Symptomatic congenital cytomegalovirus infection in infants born to mothers with preexisting immunity to cytomegalovirus. Pediatrics (1999) 104(1 Pt 1):55-60.
24. Rivera LB, Boppana SB, Fowler KB, Britt WJ, Stagno S, Pass RF: Predictors of hearing loss in children with symptomatic congenital cytomegalovirus infection. Pediatrics (2002) 110(4):762-767.
25. Stagno S, Cloud GA: Changes in the epidemiology of cytomegalovirus. Adv Exp Med Biol (1990) 278:93-104.
26. Biron KK: Antiviral drugs for cytomegalovirus diseases. Antiviral Res (2006) 71(2-3):154-163. •• An important guide to antiviral therapies for CMV and anti-CMV drugs currently in clinical develpoment.
27. Paya C, Humar A, Dominguez E, Washburn K, Blumberg E, Alexander B, Freeman R, Heaton N, Pescovitz MD: Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant (2004) 4(4):611-620.
28. Razonable RR, Paya CV: Valganciclovir for the prevention and treatment of cytomegalovirus disease in immunocompromised hosts. Expert Rev Anti Infect Ther (2004) 2(1):27-41.
29. Wiltshire H, Paya CV, Pescovitz MD, Humar A, Dominguez E, Washburn K, Blumberg E, Alexander B, Freeman R, Heaton N, Zuideveld KP: Pharmacodynamics of oral ganciclovir and valganciclovir in solid organ transplant recipients. Transplantation (2005) 79(11):1477-1483.
30. Wiltshire H, Hirankarn S, Farrell C, Paya C, Pescovitz MD, Humar A, Dominguez E, Washburn K, Blumberg E, Alexander B, Freeman R, Heaton N: Pharmacokinetic profile of ganciclovir after its oral administration and from its prodrug, valganciclovir, in solid organ transplant recipients. Clin Pharmacokinet (2005) 44(5):495-507.
31. De Clercq E, Holý A: Acyclic nucleoside phosphonates: A key class of antiviral drugs. Nat Rev Drug Discov (2005) 4(11):928-940. •• A good review on the activity of the different classes of ANPs, the discovery of which represented a breakthrough in the treatment of DNA viruses and retroviruses.
32. Snoeck R, De Clercq E: Role of cidofovir in the treatment of DNA virus infections, other than CMV infections, in immunocompromised patients. Curr Opin Investig Drugs (2002) 3(11):1561-1566.
33. Gilbert C, Boivin G: Human cytomegalovirus resistance to antiviral drugs. Antimicrob Agents Chemother (2005) 49(3):873-883.
34. Chou S: Antiviral drug resistance in human cytomegalovirus. Transpl Infect Dis (1999) 1(2):105-114. •• A comprehensive overview of the mechanisms of CMV resistance to antiviral drugs.
35. Boivin G, Gilbert C, Gaudreau A, Greenfield I, Sudlow R, Roberts NA: Rate of emergence of cytomegalovirus (CMV) mutations in leukocytes of patients with acquired immunodeficiency syndrome who are receiving valganciclovir as induction and maintenance therapy for CMV retinitis. J Infect Dis (2001) 184(12):1598-1602.
36. Limaye AP, Corey L, Koelle DM, Davis CL, Boeckh M: Emergence of ganciclovir-resistant cytomegalovirus disease among recipients of solid-organ transplants. Lancet (2000) 356(9230):645-649.
37. Eckle T, Lang P, Prix L, Jahn G, Klingebiel T, Handgretinger R, Selle B, Niethammer D, Hamprecht K: Rapid development of ganciclovir-resistant cytomegalovirus infection in children after allogeneic stem cell transplantation in the early phase of immune cell recovery. Bone Marrow Transplant (2002) 30(7):433-439.
38. Scott GM, Weinberg A, Rawlinson WD, Chou S: Multidrug resistance conferred by novel DNA polymerase mutations in human cytomegalovirus isolates. Antimicrob Agents Chemother (2007) 51(1):89-94.
39. Galli L, Novelli A, Chiappini E, Gervaso P, Cassetta MI, Fallani S, de Martino M: Valganciclovir for congenital CMV infection: A pilot study on plasma concentration in newborns and infants. Pediatr Infect Dis J (2007) 26(5):451-453.
40. Meine Jansen CF, Toet MC, Rademaker CM, Ververs TF, Gerards LJ, van Loon AM: Treatment of symptomatic congenital cytomegalovirus infection with valganciclovir. J Perinat Med (2005) 33(4):364-366.
41. Kinzler ER, Compton T: Characterization of human cytomegalovirus glycoprotein-induced cell-cell fusion. J Virol (2005) 79(12):7827-7837.
42. Lopper M, Compton T: Coiled-coil domains in glycoproteins B and H are involved in human cytomegalovirus membrane fusion. J Virol (2004) 78(15):8333-8341.
43. English EP, Chumanov RS, Gellman SH, Compton T: Rational development of ?-peptide inhibitors of human cytomegalovirus entry. J Biol Chem (2006) 281(5):2661-2667.
44. Jones TR, Lee SW, Johann SV, Razinkov V, Visalli RJ, Feld B, Bloom JD, O'Connell J: Specific inhibition of human cytomegalovirus glycoprotein B-mediated fusion by a novel thiourea small molecule. J Virol (2004) 78(3):1289-1300.
45. Vaillancourt VA, Cudahy MM, Staley SA, Brideau RJ, Conrad SJ, Knechtel ML, Oien NL, Wieber JL, Yagi Y, Wathen MW: Naphthalene carboxamides as inhibitors of human cytomegalovirus DNA polymerase. Bioorg Med Chem Lett (2000) 10(18):2079-2081.
46. Tucker JA, Clayton TL, Chidester CG, Schulz MW, Harrington LE, Conrad SJ, Yagi Y, Oien NL, Yurek D, Kuo MS: Structure-activity relationships of acyloxyamidine cytomegalovirus DNA polymerase inhibitors. Bioorg Med Chem (2000) 8(3):601-615.
47. Brideau RJ, Knechtel ML, Huang A, Vaillancourt VA, Vera EE, Oien NL, Hopkins TA, Wieber JL, Wilkinson KF, Rush BD, Schwende FJ 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.
48. Oien NL, Brideau RJ, Hopkins TA, Wieber JL, Knechtel ML, Shelly JA, Anstadt RA, Wells PA, Poorman RA, Huang A, Vaillancourt VA et al: Broad-spectrum antiherpes activities of 4-hydroxyquinoline carboxamides, a novel class of herpesvirus polymerase inhibitors. Antimicrob Agents Chemother (2002) 46(3):724-730.
49. Wathen MW: Non-nucleoside inhibitors of herpesviruses. Rev Med Virol (2002) 12(3):167-178.
50. Thomsen DR, Oien NL, Hopkins TA, Knechtel ML, Brideau RJ, Wathen MW, Homa FL: 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):1868-1876.
51. Liu S, Knafels JD, Chang JS, Waszak GA, Baldwin ET, Deibel MR, Thomsen DR, Homa FL, Wells PA, Tory MC, Poorman RA et al: Crystal structure of the herpes simplex virus 1 DNA polymerase. J Biol Chem (2006) 281(26):18193-18200.
52. Schnute ME, Cudahy MM, Brideau RJ, Homa FL, Hopkins TA, Knechtel ML, Oien NL, Pitts TW, Poorman RA, Wathen MW, Wieber JL: 4-Oxo-4,7-dihydrothieno[2,3- b]pyridines as non-nucleoside inhibitors of human cytomegalovirus and related herpesvirus polymerases. J Med Chem (2005) 48(18):5794-5804.
53. Schnute ME, Anderson DJ, Brideau RJ, Ciske FL, Collier SA, Cudahy MM, Eggen M, Genin MJ, Hopkins TA, Judge TM, Kim EJ et al: 2-Aryl-2-hydroxyethylamine substituted 4-oxo-4,7-dihydrothieno[2,3-b] pyridines as broad-spectrum inhibitors of human herpesvirus polymerases. Bioorg Med Chem Lett (2007) 17(12):3349-3353.
54. Larsen SD, Zhang Z, Dipaolo BA, Manninen PR, Rohrer DC, Hageman MJ, Hopkins TA, Knechtel ML, Oien NL, Rush BD, Schwende FJ et al: 7-Oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamides: Synthesis and biological activity of a new class of highly potent inhibitors of human cytomegalovirus DNA polymerase. Bioorg Med Chem Lett (2007) 17(14):3840-3844.
55. Beadle JR, Hartline C, Aldern KA, Rodriguez N, Harden E, Kern ER, Hostetler KY: Alkoxyalkyl esters of cidofovir and cyclic cidofovir exhibit multiple-log enhancement of antiviral activity against cytomegalovirus and herpesvirus replication in vitro. Antimicrob Agents Chemother (2002) 46(8):2381-2386.
56. Ciesla SL, Trahan J, Wan WB, Beadle JR, Aldern KA, Painter GR, Hostetler KY: Esterification of cidofovir with alkoxyalkanols increases oral bioavailability and diminishes drug accumulation in kidney. Antiviral Res (2003) 59(3):163-171.
57. Kern ER, Collins DJ, Wan WB, Beadle JR, Hostetler KY, Quenelle DC: Oral treatment of murine cytomegalovirus infections with ether lipid esters of cidofovir. Antimicrob Agents Chemother (2004) 48(9):3516- 3522.
58. Painter GR, Hostetler KY: Design and development of oral drugs for the prophylaxis and treatment of smallpox infection. Trends Biotechnol (2004) 22(8):423-427.
59. De Clercq E: The acyclic nucleoside phosphonates from inception to clinical use: Historical perspective. Antiviral Res (2007) 75(1):1-13.
60. Balzarini J, Pannecouque C, Naesens L, Andrei G, Snoeck R, De Clercq E, Hocková D, Holý A: 6-[2-(Phosphonomethoxy)alkoxy]-2,4- diaminopyrimidines: A new class of acyclic pyrimidine nucleoside phosphonates with antiviral activity. Nucleosides Nucleotides Nucleic Acids (2004) 23(8-9):1321-1327.
61. Hocková D, Holý A, Masojídková M, Andrei G, Snoeck R, De Clercq E, Balzarini J: 5-Substituted-2,4-diamino-6-[2- (phosphonomethoxy)ethoxy]pyrimidines-acyclic nucleoside phosphonate analogues with antiviral activity. J Med Chem (2003) 46(23):5064-5073.
62. Hocková D, Holý A, Masojídková M, Andrei G, Snoeck R, De Clercq E, Balzarini J: Synthesis and antiviral activity of 2,4-diamino-5-cyano-6-[2-(phosphonomethoxy)ethoxy]pyrimidine and related compounds. Bioorg Med Chem (2004) 12(12):3197-3202.
63. De Clercq E, Andrei G, Balzarini J, Leyssen P, Naesens L, Neyts J, Pannecouque C, Snoeck R, Ying C, Hocková D, Holý A: Antiviral potential of a new generation of acyclic nucleoside phosphonates, the 6-[2-(phosphonomethoxy)alkoxy]-2,4-diaminopyrimidines. Nucleosides Nucleotides Nucleic Acids (2005) 24(5-7):331-341.
64. Krecmerová M, Holý A, Pískala A, Masojídková M, Andrei G, Naesens L, Neyts J, Balzarini J, De Clercq E, Snoeck R: Antiviral activity of triazine analogues of 1-(S)-[3-hydroxy-2-(phosphonomethoxy) propyl]cytosine (cidofovir) and related compounds. J Med Chem (2007) 50(5):1069-1077.
65. Krecmerova M, Holy A, Piskala A, Masojidkova M, Andrei G, Naesens L, Neyts J, Balzarini J, De Clercq E, Snoeck R: Ester prodrugs of cyclic 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine: Synthesis and antiviral activity. J Med Chem (2007) 50(23):5765-5772.
66. Spector FC, Liang L, Giordano H, Sivaraja M, Peterson MG: Inhibition of herpes simplex virus replication by a 2-amino thiazole via interactions with the helicase component of the UL5-UL8-UL52 complex. J Virol (1998) 72(9):6979-6987.
67. Kleymann G, Fischer R, Betz UA, Hendrix M, Bender W, Schneider U, Handke G, Eckenberg P, Hewlett G, Pevzner V, Baumeister J et al: New helicase-primase inhibitors as drug candidates for the treatment of herpes simplex disease. Nat Med (2002) 8(4):392-398.
68. Baumeister J, Fischer R, Eckenberg P, Henninger K, Ruebsamen-Waigmann H, Kleymann G: Superior efficacy of helicase-primase inhibitor BAY 57-1293 for herpes infection and latency in the guinea pig model of human genital herpes disease. Antivir Chem Chemother (2007) 18(1):35-48.
69. Crute JJ, Grygon CA, Hargrave KD, Simoneau B, Faucher AM, Bolger G, Kibler P, Liuzzi M, Cordingley MG: Herpes simplex virus helicase-primase inhibitors are active in animal models of human disease. Nat Med (2002) 8(4):386-391.
70. Kleymann G: New antiviral drugs that target herpesvirus helicase primase enzymes. Herpes (2003) 10(2):46-52.
71. Liuzzi M, Kibler P, Bousquet C, Harji F, Bolger G, Garneau M, Lapeyre N, McCollum RS, Faucher AM, Simoneau B, Cordingley MG: Isolation and characterization of herpes simplex virus type 1 resistant to aminothiazolylphenyl-based inhibitors of the viral helicase-primase. Antiviral Res (2004) 64(3):161-170.
72. Coen DM, Schaffer PA: Antiherpesvirus drugs: A promising spectrum of new drugs and drug targets. Nat Rev Drug Discov (2003) 2(4):278-288.
73. Tularik Inc: Tularik provides mid-year update at the 23rd Annual Goldman Sachs Healthcare Conference. Press Release (2002): June 11.
74. Chen X, Adrian J, Cushing T, Dimaio H, Liang L, Mayorga V, Miao S, Peterson MG, Powers JP, Spector F, Stein C et al: SAR studies on a novel series of human cytomegalovirus primase inhibitors. Bioorg Med Chem Lett (2007) 17(8):2188-2192.
75. Cushing TD, Adrian J, Chen X, DiMaio H, Doughan B, Flygare J, Liang L, Mayorga V, Miao S, Mellon H, Peterson MG et al: Discovery of a novel series of inhibitors of human cytomegalovirus primase. Bioorg Med Chem Lett (2006) 16(18):4879-4883.
76. Loregian A, Rigatti R, Murphy M, Schievano E, Palu G, Marsden HS: Inhibition of human cytomegalovirus DNA polymerase by C-terminal peptides from the UL54 subunit. J Virol (2003) 77(15):8336-8344.
77. Hannon GJ: RNA interference. Nature (2002) 418(6894):244-251.
78. Leonard JN, Schaffer DV: Antiviral RNAi therapy: Emerging approaches for hitting a moving target. Gene Ther (2006) 13(6):532-540.
79. Silva JM, Hammond SM, Hannon GJ: RNA interference: A promising approach to antiviral therapy? Trends Mol Med (2002) 8(11):505-508.
80. Dykxhoorn DM, Lieberman J: Silencing viral infection. PLoS Med (2006) 3(7):e242. •• A good review of RNAi as an approach to antiviral therapy.
81. Wiebusch L, Truss M, Hagemeier C: Inhibition of human cytomegalovirus replication by small interfering RNAs. J Gen Virol (2004) 85(1):179-184.
82. Shin MC, Hong SK, Yoon JS, Park SS, Lee SG, Lee DG, Min WS, Shin WS, Paik SY: Inhibition of UL54 and UL97 genes of human cytomegalovirus by RNA interference. Acta Virol (2006) 50(4):263-268.
83. Reefschlaeger J, Bender W, Hallenberger S, Weber O, Eckenberg P, Goldmann S, Haerter M, Buerger I, Trappe J, Herrington JA, Haebich D 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):757-767.
84. Buerger I, Reefschlaeger J, Bender W, Eckenberg P, Popp A, Weber O, Graeper S, Klenk HD, Ruebsamen-Waigmann H, Hallenberger S: A novel nonnucleoside inhibitor specifically targets cytomegalovirus DNA maturation via the UL89 and UL56 gene products. J Virol (2001) 75(19):9077- 9086.
85. Bogner E: Human cytomegalovirus terminase as a target for antiviral chemotherapy. Rev Med Virol (2002) 12(2):115-127.
86. McSharry JJ, McDonough A, Olson B, Hallenberger S, Reefschlaeger J, Bender W, Drusano GL: Susceptibilities of human cytomegalovirus clinical isolates to BAY38-4766, BAY43-9695, and ganciclovir. Antimicrob Agents Chemother (2001) 45(10):2925-2927.
87. Schleiss MR, Bernstein DI, McVoy MA, Stroup G, Bravo F, Creasy B, McGregor A, Henninger K, Hallenberger S: The non-nucleoside antiviral, BAY 38-4766, protects against cytomegalovirus (CMV) disease and mortality in immunocompromised guinea pigs. Antiviral Res (2005) 65(1):35-43.
88. Bayer AG: Drug development pipelines: BAY-19-8004, BAY-27-9955, BAY-38-1315, BAY-41-7307, BAY-38-4766, BAY-W-9279. Company Communication (2000):November 30.
89. Townsend LB, Devivar RV, Turk SR, Nassiri MR, Drach JC: Design, synthesis, and antiviral activity of certain 2,5,6-trihalo-1-(β-D- ribofuranosyl)benzimidazoles. J Med Chem (1995) 38(20):4098- 4105.
90. Underwood MR, Harvey RJ, Stanat SC, Hemphill ML, Miller T, Drach JC, Townsend LB, Biron KK: Inhibition of human cytomegalovirus DNA maturation by a benzimidazole ribonucleoside is mediated through the UL89 gene product. J Virol (1998) 72(1):717-725.
91. Krosky PM, Underwood MR, Turk SR, Feng KW, Jain RK, Ptak RG, Westerman AC, Biron KK, Townsend LB, Drach JC: Resistance of human cytomegalovirus to benzimidazole ribonucleosides maps to two open reading frames: UL89 and UL56. J Virol (1998) 72(6):4721-4728.
92. Dittmer A, Bogner E: Analysis of the quaternary structure of the putative HCMV portal protein PUL104. Biochemistry (2005) 44(2):759-765.
93. Dittmer A, Drach JC, Townsend LB, Fischer A, Bogner E: Interaction of the putative human cytomegalovirus portal protein pUL104 with the large terminase subunit pUL56 and its inhibition by benzimidazole-D- ribonucleosides. J Virol (2005) 79(23):14660-14667.
94. Krosky PM, Baek MC, Coen DM: The human cytomegalovirus UL97 protein kinase, an antiviral drug target, is required at the stage of nuclear egress. J Virol (2003) 77(2):905-914.
95. Biron KK, Harvey RJ, Chamberlain SC, Good SS, Smith AA, Davis MG, Talarico CL, Miller WH, Ferris R, Dornsife RE, Stanat SC et al: Potent and selective inhibition of human cytomegalovirus replication by 1263W94, a benzimidazole L-riboside with a unique mode of action. Antimicrob Agents Chemother (2002) 46(8):2365-2372.
96. Chou S, Wechel LC, Marousek GI: Cytomegalovirus UL97 kinase mutations that confer maribavir resistance. J Infect Dis (2007) 196(1):91-94. • One of the most recent studies concerning the mechanism of resistance to maribavir.
97. Wolf DG, Courcelle CT, Prichard MN, Mocarski ES: Distinct and separate roles for herpesvirus-conserved UL97 kinase in cytomegalovirus DNA synthesis and encapsidation. Proc Natl Acad Sci USA (2001) 98(4):1895- 1900.
98. Krosky PM, Baek MC, Jahng WJ, Barrera I, Harvey RJ, Biron KK, Coen DM, Sethna PB: The human cytomegalovirus UL44 protein is a substrate for the UL97 protein kinase. J Virol (2003) 77(14):7720-7727.
99. Chou S, Marousek GI: Maribavir antagonizes the antiviral action of ganciclovir on human cytomegalovirus. Antimicrob Agents Chemother (2006) 50(10):3470-3472.
100. Komazin G, Ptak RG, Emmer BT, Townsend LB, Drach JC: Resistance of human cytomegalovirus to the benzimidazole L-ribonucleoside maribavir maps to UL27. J Virol (2003) 77(21):11499-11506.
101. Drew WL, Miner RC, Marousek GI, Chou S: Maribavir sensitivity of cytomegalovirus isolates resistant to ganciclovir, cidofovir or foscarnet. J Clin Virol (2006) 37(2):124-127.
102. Lalezari JP, Aberg JA, Wang LH, Wire MB, Miner R, Snowden W, Talarico CL, Shaw S, Jacobson MA, Drew WL: Phase I dose 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):2969-2976.
103. Lu H, Thomas S: Maribavir (ViroPharma). Curr Opin Investig Drugs (2004) 5(8):898-906.
104. Zimmermann A, Wilts H, Lenhardt M, Hahn M, Mertens T: Indolocarbazoles exhibit strong antiviral activity against human cytomegalovirus and are potent inhibitors of the pUL97 protein kinase. Antiviral Res (2000) 48(1):49-60.
105. Slater MJ, Baxter R, Bonser RW, Cockerill S, Gohil K, Parry N, Robinson E, Randall R, Yeates C, Snowden W, Walters A: Synthesis of N-alkyl substituted indolocarbazoles as potent inhibitors of human cytomegalovirus replication. Bioorg Med Chem Lett (2001) 11(15):1993-1995.
106. Slater MJ, Cockerill S, Baxter R, Bonser RW, Gohil K, Gowrie C, Robinson JE, Littler E, Parry N, Randall R, Snowden W: Indolocarbazoles: Potent, selective inhibitors of human cytomegalovirus replication. Bioorg Med Chem (1999) 7(6):1067-1074.
107. Marschall M, Stein-Gerlach M, Freitag M, Kupfer R, van den Bogaard M, Stamminger T: Direct targeting of human cytomegalovirus protein kinase pUL97 by kinase inhibitors is a novel principle for antiviral therapy. J Gen Virol (2002) 83(5):1013-1023.
108. Qiu X, Culp JS, DiLella AG, Hellmig B, Hoog SS, Janson CA, Smith WW, Abdel-Meguid SS: Unique fold and active site in cytomegalovirus protease. Nature (1996) 383(6597):275-279.
109. Chen P, Tsuge H, Almassy RJ, Gribskov CL, Katoh S, Vanderpool DL, Margosiak SA, Pinko C, Matthews DA, Kan CC: Structure of the human cytomegalovirus protease catalytic domain reveals a novel serine protease fold and catalytic triad. Cell (1996) 86(5):835-843.
110. Flynn DL, Abood NA, Holwerda BC: Recent advances in antiviral research: Identification of inhibitors of the herpesvirus proteases. Curr Opin Chem Biol (1997) 1(2):190-196.
111. Borthwick AD, Davies DE, Ertl PF, Exall AM, Haley TM, Hart GJ, Jackson DL, Parry NR, Patikis A, Trivedi N, Weingarten GG et al: Design and synthesis of pyrrolidine-5,5′-trans-lactams (5-oxo-hexahydropyrrolo[3,2- b]pyrroles) as novel mechanism-based inhibitors of human cytomegalovirus protease. 4. Antiviral activity and plasma stability. J Med Chem (2003) 46(21):4428-4449. • A detailed study describing the drug discovery program used to identify HCMV protease inhibitors.
112. Borthwick AD: Design of translactam HCMV protease inhibitors as potent antivirals. Med Res Rev (2005) 25(4):427-452.
113. Gerona-Navarro G, Pérez de Vega MJ, García-López MT, Andrei G, Snoeck R, Balzarini J, De Clercq E, González-Muñiz R: Synthesis and anti-HCMV activity of 1-acyl-β-lactams and 1-acylazetidines derived from phenylalanine. Bioorg Med Chem Lett (2004) 14(9):2253-2256.
114. Gerona-Navarro G, Pérez de Vega MJ, García-López MT, Andrei G, Snoeck R, De Clercq E, Balzarini J, González-Muñiz R: From 1-acyl-β-lactam human cytomegalovirus protease inhibitors to 1-benzyloxycarbonylazetidines with improved antiviral activity. A straightforward approach to convert covalent to noncovalent inhibitors. J Med Chem (2005) 48(7):2612-2621.
115. Hulshof JW, Casarosa P, Menge WM, Kuusisto LM, van der GH, Smit MJ, de Esch IJ, Leurs R: Synthesis and structure-activity relationship of the first nonpeptidergic inverse agonists for the human cytomegalovirus encoded chemokine receptor US28. J Med Chem (2005) 48(20):6461-6471.
116. Hulshof JW, Vischer HF, Verheij MH, Fratantoni SA, Smit MJ, de Esch IJ, Leurs R: Synthesis and pharmacological characterization of novel inverse agonists acting on the viral-encoded chemokine receptor US28. Bioorg Med Chem (2006) 14(21):7213-7230.
117. Snoeck R, Andrei G, Bodaghi B, Lagneaux L, Daelemans D, de Clercq E, Neyts J, Schols D, Naesens L, Michelson S, Bron D et al: 2-Chloro-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxamide (CMV423), a new lead compound for the treatment of human cytomegalovirus infections. Antiviral Res (2002) 55(3):413-424.
118. De Bolle L, Andrei G, Snoeck R, Zhang Y, Van Lommel A, Otto M, Bousseau A, Roy C, De Clercq E, Naesens L: Potent, selective and cell-mediated inhibition of human herpesvirus 6 at an early stage of viral replication by the non-nucleoside compound CMV423. Biochem Pharmacol (2004) 67(2):325-336.
119. Hayashi K, Minoda K, Nagaoka Y, Hayashi T, Uesato S: Antiviral activity of berberine and related compounds against human cytomegalovirus. Bioorg Med Chem Lett (2007) 17(6):1562-1564.
120. Naesens L, Stephens CE, Andrei G, Loregian A, De Bolle L, Snoeck R, Sowell JW, De Clercq E: Antiviral properties of new arylsulfone derivatives with activity against human betaherpesviruses. Antiviral Res (2006) 72(1):60-67.
121. McGuigan C, Pathirana RN, Snoeck R, Andrei G, De Clercq E, Balzarini J: Discovery of a new family of inhibitors of human cytomegalovirus (HCMV) based upon lipophilic alkyl furano pyrimidine dideoxy nucleosides: Action via a novel non-nucleosidic mechanism. J Med Chem (2004) 47(7):1847-1851.
122. Schang LM: Cyclin-dependent kinases as cellular targets for antiviral drugs. J Antimicrob Chemother (2002) 50(6):779-792.
123. Schang LM, St Vincent MR, Lacasse JJ: Five years of progress on cyclin-dependent kinases and other cellular proteins as potential targets for antiviral drugs. Antivir Chem Chemother (2006) 17(6):293-320. • A detailed review on CDKs as cellular targets for antiviral drugs, highlighting the importance of host cell protein kinases in viral replication.
124. Davido DJ, Leib DA, Schaffer PA: The cyclin-dependent kinase inhibitor roscovitine inhibits the transactivating activity and alters the posttranslational modification of herpes simplex virus type 1 ICP0. J Virol (2002) 76(3):1077-1088.
125. Taylor SL, Kinchington PR, Brooks A, Moffat JF: Roscovitine, a cyclin-dependent kinase inhibitor, prevents replication of varicella-zoster virus. J Virol (2004) 78(6):2853-2862.
126. Sanchez V, McElroy AK, Yen J, Tamrakar S, Clark CL, Schwartz RA, Spector DH: Cyclin-dependent kinase activity is required at early times for accurate processing and accumulation of the human cytomegalovirus UL122-123 and UL37 immediate-early transcripts and at later times for virus production. J Virol (2004) 78(20):11219-11232.
127. Sanchez V, Spector DH: Cyclin-dependent kinase activity is required for efficient expression and posttranslational modification of human cytomegalovirus proteins and for production of extracellular particles. J Virol (2006) 80(12):5886-5896.
128. Hertel L, Mocarski ES: Global analysis of host cell gene expression late during cytomegalovirus infection reveals extensive dysregulation of cell cycle gene expression and induction of pseudomitosis independent of US28 function. J Virol (2004) 78(21):11988-12011.
129. Hertel L, Chou S, Mocarski ES: Viral and cell cycle-regulated kinases in cytomegalovirus-induced pseudomitosis and replication. PLoS Pathog (2007) 3(1):e6.
130. Schang LM: First demonstration of the effectiveness of inhibitors of cellular protein kinases in antiviral therapy. Expert Rev Anti Infect Ther (2006) 4(6):953-956.
131. Yang H, Kim SK, Kim M, Reche PA, Morehead TJ, Damon IK, Welsh RM, Reinherz EL: Antiviral chemotherapy facilitates control of poxvirus infections through inhibition of cellular signal transduction. J Clin Invest (2005) 115(2):379-387.
132. Reeves PM, Bommarius B, Lebeis S, McNulty S, Christensen J, Swimm A, Chahroudi A, Chavan R, Feinberg MB, Veach D, Bornmann W et al: Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases. Nat Med (2005) 11(7):731-739.
133. Koon HB, Bubley GJ, Pantanowitz L, Masiello D, Smith B, Crosby K, Proper J, Weeden W, Miller TE, Chatis P, Egorin MJ et al: Imatinib-induced regression of AIDS-related Kaposi's sarcoma. J Clin Oncol (2005) 23(5):982-989.
134. DeFilippis V, Raggo C, Moses A, Früh K: Functional genomics in virology and antiviral drug discovery. Trends Biotechnol (2003) 21(10):452-457.
135. Browne EP, Wing B, Coleman D, Shenk T: Altered cellular mRNA levels in human cytomegalovirus-infected fibroblasts: Viral block to the accumulation of antiviral mRNAs. J Virol (2001) 75(24):12319-12330.
136. Zhu H, Cong JP, Yu D, Bresnahan WA, Shenk TE: Inhibition of cyclooxygenase 2 blocks human cytomegalovirus replication. Proc Natl Acad Sci USA (2002) 99(6):3932-3937.
137. Coux O, Tanaka K, Goldberg AL: Structure and functions of the 20S and 26S proteasomes. Annu Rev Biochem (1996) 65:801-847.
138. Rivett AJ, Gardner RC: Proteasome inhibitors: From in vitro uses to clinical trials. J Pept Sci (2000) 6(9):478-488.
139. Goldberg AL, Rock K: Not just research tools - proteasome inhibitors offer therapeutic promise. Nat Med (2002) 8(4):338-340. • A good review on the use of proteasome inhibitors as therapeutics. Proteasome inhibitors have been widely used as anticancer drugs and in animal models for inflammation-associated diseases.
140. Prösch S, Priemer C, Höflich C, Liebenthaf C, Babel N, Krüger DH, Volk HD: Proteasome inhibitors: A novel tool to suppress human cytomegalovirus replication and virus-induced immune modulation. Antivir Ther (2003) 8(6):555-567.
141. La Frazia S, Amici C, Santoro MG: Antiviral activity of proteasome inhibitors in herpes simplex virus-1 infection: Role of nuclear factor-κB. Antivir Ther (2006) 11(8):995-1004.