Another ten stories inantiviraldrug discovery (Part C): "Old" and "new" antivirals, strategies, and perspectives

Medicinal Research Reviews

Volumn 29, Issue 4, 2009, Pages 611-645

  De Clercq, Erik ^a  

^a REGA INSTITUTE FOR MEDICAL RESEARCH   (Belgium)

Author keywords

Acyclovir; Amantadine; Cidofovir; Cyclopent(en)ylcytosine (C Cyd and Ce Cyd); Deoxyuridine derivatives (IDU, TFT); Pyrazofurin; Ribavirin; Rilpivirine; SAH hydrolase inhibitors; ST 246; Tenofovir disoproxil fumarate (TDF, Viread )

Indexed keywords

1 (4,5 DIHYDROXY 3 HYDROXYMETHYL 2 CYCLOPENTEN 1 YL)CYTOSINE; 3 DEAZAADENOSINE; 3 DEAZANEPLANOCIN A; 5 (2 BROMOVINYL) 2' DEOXYURIDINE; 5 ETHYNYL 4 IMIDAZOLECARBOXAMIDE 1 RIBOSIDE; 9 (2,3 DIHYDROXYPROPYL)ADENINE; 9 [1,2 BIS(HYDROXYMETHYL)CYCLOPROPYLMETHYL]GUANINE; ACICLOVIR; ACYCLIC NUCLEOSIDE; ADEFOVIR DIPIVOXIL; ADENOSYLHOMOCYSTEINASE; ADENOSYLHOMOCYSTEINASE INHIBITOR; AMANTADINE; AMANTADINE DERIVATIVE; ANTIVIRUS AGENT; BRIVIRAC; CF 1743; CIDOFOVIR; DEOXYURIDINE DERIVATIVE; EFAVIRENZ PLUS EMTRICITABINE PLUS TENOFOVIR DISOPROXIL; EMTRICITABINE PLUS TENOFOVIR DISOPROXIL; ETRAVIRINE; FV 100; IDOXURIDINE; INOSINATE DEHYDROGENASE; LEVOVIRIN; MIZORIBINE; NEPLANOCIN A; PEGINTERFERON ALPHA2A; R 106168; RIBAVIRIN; RILPIVIRINE; RIMANTADINE; SPIRO(CYCLOPROPANE 1,2' ADAMANTAN) 2 METHYLAMINE; SPIRO(PYRROLIDINE 2,2' ADAMANTANE); ST 246; TARIBAVIRIN; TENOFOVIR DISOPROXIL; TIVIRAPINE; TRIFLURIDINE; UNCLASSIFIED DRUG; UNINDEXED DRUG; VALACICLOVIR; ZERPEX; ZOSTEX; PROTEINASE INHIBITOR;

DRUG DOSE REDUCTION; DRUG EFFECT; DRUG EFFICACY; DRUG RESEARCH; DRUG TARGETING; ENZYME INHIBITION; HEPATITIS B; HEPATITIS C; HERPES LABIALIS; HERPES SIMPLEX; HERPES SIMPLEX KERATITIS; HERPES ZOSTER; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; INFLUENZA; INFLUENZA VIRUS A; LASSA FEVER; NONHUMAN; POXVIRUS INFECTION; REVIEW; VIRUS INFECTION; DRUG ANTAGONISM; DRUG DEVELOPMENT; VIROLOGY;

ANTIVIRAL AGENTS; DRUG DISCOVERY; HEPATITIS C, CHRONIC; HIV PROTEASE INHIBITORS; IMP DEHYDROGENASE; RIBAVIRIN;

EID: 67649744219     PISSN: 01986325     EISSN: None     Source Type: Journal    
DOI: 10.1002/med.20153     Document Type: Review

References (207)

1. De Clercq E. The discovery of antiviral agents: Ten different compounds, ten different stories. Med Res Rev 2008;28:929-953.
2. De Clercq E. Antiviral drug discovery: Ten more compounds, and ten more stories (part B). Med Res Rev 2009, in press.
3. Sidwell RW, Huffman JH, Khare GP, Allen LB, Witkowski JT, Robins RK. Broad-spectrum antiviral activity of Virazole: 1-beta-D-ribofuranosyl-1,2,4- triazole-3-carboxamide. Science 1972;177:705-706.
4. Witkowski JT, Robins RK, Sidwell RW, Simon LN. Design, synthesis, and broad spectrum antiviral activity of 1-β-D-ribofuranosyl-1,2,4-triazole-3- carboxamide and related nucleosides. J Med Chem 1972;15:1150-1154.
5. Streeter DG, Witkowski JT, Khare GP, Sidwell RW, Bauer RJ, Robins RK, Simon LN. Mechanism of action of 1-β-D-ribofuranosyl-1,2,4-triazole-3- carboxamide (Virazole), a new broad-spectrum antiviral agent. Proc Natl Acad Sci USA 1973;70:1174-1178.
6. Potter CW, Phair JP, Vodinelich L, Fenton R, Jennings R. Antiviral, immunosuppressive and antitumour effects of ribavirin. Nature 1976;259:496-497.
7. Boeckh M, Englund J, Li Y, Miller C, Cross A, Fernandez H, Kuypers J, Kim H, Gnann J, Whitley R. Randomized controlled multicenter trial of aerosolized ribavirin for respiratory syncytial virus upper respiratory tract infection in hematopoietic cell transplant recipients. Clin Infect Dis 2007;44:245-249. (Pubitemid 46079989)
8. Torres HA, Aguilera EA, Mattiuzzi GN, Cabanillas ME, Rohatgi N, Sepulveda CA, Kantarjian HM, Jiang Y, Safdar A, Raad II, Chemaly RF. Characteristics and outcome of respiratory syncytial virus infection in patients with leukemia. Haematologica 2007;92:1216-1223. (Pubitemid 350144180)
9. Raza K, Ismailjee SB, Crespo M, Studer SM, Sanghavi S, Paterson DL, Kwak EJ, Rinaldo Jr CR, Pilewski JM, McCurry KR, Husain S. Successful outcome of human metapneumovirus (hMPV) pneumonia in a lung transplant recipient treated with intravenous ribavirin. J Heart Lung Transplant 2007;26:862-864. (Pubitemid 47199078)
10. Gilbert BE, McLeay MT. Megaribavirin aerosol for the treatment of influenza A virus infections in mice. Antiviral Res 2008;78:223-229.
11. McCormick JB, King IJ, Webb PA, Scribner CL, Craven BB, Johnson KM, Elliott LH, Belmont-Williams R. Lassa fever. Effective therapy with ribavirin. N Engl J Med 1986;314:20-26. (Pubitemid 16183064)
12. Khan SH, Goba A, Chu M, Roth C, Healing T, Marx A, Fair J, Guttieri MC, Ferro P, Imes T, Monagin C, Garry RF, Bausch DG. New opportunities for field research on the pathogenesis and treatment of Lassa fever. Antiviral Res 2008;78:103-115.
13. Enria DA, Briggiler AM, Sánchez Z. Treatment of Argentine hemorrhagic fever. Antiviral Res 2008;78:132-139.
14. Andrei G, De Clercq E. Inhibitory effect of selected antiviral compounds on arenavirus replication in vitro. Antiviral Res 1990;14:287-300. (Pubitemid 20377566)
15. Monath TP. Treatment of yellow fever. Antiviral Res 2008;78:116-124.
16. Jonsson CB, Hooper J, Mertz G. Treatment of hantavirus pulmonary syndrome. Antiviral Res 2008;78:162-169.
17. Huggins JW, Hsiang CM, Cosgriff TM, Guang MY, Smith JI, Wu ZO, LeDuc JW, Zheng ZM, Meegan JM, Wang QN. Prospective, double-blind, concurrent, placebo-controlled clinical trial of intravenous ribavirin therapy of hemorrhagic fever with renal syndrome. J Infect Dis 1991; 164:1119-1127.
18. Chapman LE, Mertz GJ, Peters CJ, Joison HM, Khan AS, Ksiazek TG, Koster FT, Baum KF, Rollin PE, Pavia AT, Holman RC, Christenson JC, Rubin PJ, Behrman RE, Bell LJ, Simpson GL, Sadek RF. Intravenous ribavirin for hantavirus pulmonary syndrome: Safety and tolerance during 1 year of open-label experience. Ribavirin Study Group. Antivir Ther 1999; 4:211-219. (Pubitemid 30058021)
19. Mertz GJ, Miedzinski L, Goade D, Pavia AT, Hjelle B, Hansbarger CO, Levy H, Koster FT, Baum K, Lindemulder A, Wang W, Riser L, Fernandez H, Whitley RJ. Placebo-controlled, double-blind trial of intravenous ribavirin for the treatment of hantavirus cardiopulmonary syndrome in North America. Clin Infect Dis 2004;39:1307-1313. (Pubitemid 39458516)
20. Li ZH, Li CM, Ling P, Shen FH, Chen SH, Liu CC, Yu CK, Chen SH. Ribavirin reduces mortality in enterovirus 71-infected mice by decreasing viral replication. J Infect Dis 2008;197:854-857.
21. Livonesi MC, De Sousa RLM, Badra SJ, Figueiredo JTM. In vitro and in vivo studies of ribavirin action on Brazilian orthobunyavirus. Am J Trop Med Hyg 2006;75:1011-1016.
22. Ergonul O. Treatment of Crimean-Congo hemorrhagic fever. Antiviral Res 2008;78:125-131.
23. Crotty S, Maag D, Arnold JJ, Zhong W, Lau JY, Hong Z, Andino R, Cameron CE. The broadspectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen. Nature Med 2000;6:1375-1379. (Pubitemid 32001022)
24. Crotty S, Cameron CE, Andino R. RNA virus error catastrophe: Direct molecular test by using ribavirin. Proc Natl Acad Sci USA 2001;98:6895-6900. (Pubitemid 32538313)
25. Chang K-O, George DW. Interferons and ribavirin effectively inhibit Norwalk virus replication in replicon-bearing cells. J Virol 2007;81:12111-12118. (Pubitemid 350085826)
26. Leyssen P, De Clercq E, Neyts J. The anti-yellow fever virus activity of ribavirin is independent of error-prone replication. Mol Pharmacol 2006;69:1461-1467.
27. Leyssen P, Balzarini J, De Clercq E, Neyts J. The predominant mechanism by which ribavirin exerts its antiviral activity in vitro against flaviviruses and paramyxoviruses is mediated by inhibition of IMP dehydrogenase. J Virol 2005;79:1943-1947. (Pubitemid 40459141)
28. Sun Y, Chung D-H, Chu Y-K, Jonsson CB, Parker WB. Activity of ribavirin against Hantaan virus correlates with production of ribavirin-5′- triphosphate, not with inhibition of IMP dehydrogenase. Antimicrob Agents Chemother 2007;51:84-88. (Pubitemid 46047691)
29. Severson WE, Schmaljohn CS, Javadian A, Jonsson CB. Ribavirin causes error catastrophe during Hantaan virus replication. J Virol 2003;77:481-488. (Pubitemid 36004987)
30. Chung D-H, Sun Y, Parker WB, Arterburn JB, Bartolucci A, Jonsson CB. Ribavirin reveals a lethal threshold of allowable mutation frequency for Hantaan virus. J Virol 2007;81:11722-11729. (Pubitemid 47623804)
31. Dusheiko G, Nelson D, Reddy KR. Ribavirin considerations in treatment optimization. Antiviral Ther 2008;13:23-30. (Pubitemid 351542495)
32. Hadziyannis SJ, Sette Jr H, Morgan TR, Balan V, Diago M, Marcellin P, Ramadori G, Bodenheimer Jr H, Bernstein D, Rizzetto M, Zeuzem S, Pockros PJ, Lin A, Ackrill AM. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: A randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140:346-355. (Pubitemid 38268915)
33. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonçales Jr FL, Häussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, Lin A, Hoffman J, Yu J. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975-982.
34. Bronowicki JP, Ouzan D, Asselah T, Desmorat H, Zarski JP, Foucher J, Bourlière M, Renou C, Tran A, Melin P, Hézode C, Chevalier M, Bouvier-Alias M, Chevaliez S, Montestruc F, Lonjon-Domanec I, Pawlotsky JM. Effect of ribavirin in genotype 1 patients with hepatitis C responding to pegylated interferon alfa-2a plus ribavirin. Gastroenterology 2006;131:1040-1048. (Pubitemid 44515099)
35. Bain VG, Lee SS, Peltekian K. Exposure to ribavirin predicts EVR and SVR in patients with HCV genotype 1 infection: Analysis of the Canadian PEGASYSs Expanded Access Program. Hepatology 2006;44:335A-336A.
36. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: A randomised trial. Lancet 2001;358:958-965. (Pubitemid 32913521)
37. Fried M, Jensen D, Rodriguez-Torres M. Improved sustained virological response (SVR) rates with higher, fixed doses of peginterferon alfa-2a (40KD) (PEGASYS) plus ribavirin (RBV) (COPEGUS) in patients with difficult-to-cure characteristics. Hepatology 2006;44:314A.
38. Lindahl K, Stahle L, Bruchfeld A, Schvarcz R. High-dose ribavirin in combination with standard dose peginterferon for treatment of patients with chronic hepatitis C. Hepatology 2005;41:275-279. (Pubitemid 40165370)
39. Shiffman ML, Salvatore J, Hubbard S, Price A, Sterling RK, Stravitz RT, Luketic VA, Sanyal AJ. Treatment of chronic hepatitis C virus genotype 1 with peginterferon, ribavirin, and epoetin alpha. Hepatology 2007;46:371-379. (Pubitemid 47344771)
40. Ferenci P, Brunner H, Laferi H, Scherzer TM, Maieron A, Strasser M, Fischer G, Hofer H, Bischof M, Stauber R, Gschwantier M, Steindl-Munda P, Staufer K, Löschenberger K. A randomized, prospective trial of ribavirin 400 mg/day versus 800 mg/day in combination with peginterferon alfa-2a in hepatitis C virus genotypes 2 and 3. Hepatology 2008;47:1816-1823. (Pubitemid 351945549)
41. Loustaud-Ratti V, Alain S, Rousseau A, Hubert IF, Sauvage FL, Marquet P, Denis F, Lunel F, Calès P, Lefebvre A, Fauchais AL, Liozon E, Vidal E. Ribavirin exposure after the first dose is predictive of sustained virological response in chronic hepatitis C. Hepatology 2008;47:1453-1461. (Pubitemid 351702729)
42. Leyssen P, De Clercq E, Neyts J. Molecular strategies to inhibit the replication of RNA viruses. Antiviral Res 2008;78:9-25.
43. De Clercq E. Antivirals and antiviral strategies. Nat Rev Microbiol 2004;2:704-720. (Pubitemid 39206268)
44. Lau JY, Tam RC, Liang TJ, Hong Z. Mechanism of action of ribavirin in the combination treatment of chronic HCV infection. Hepatology 2002;35:1002-1009. (Pubitemid 34453997)
45. Pawlotsky JM, Dahari H, Neumann AU, Hezode C, Germanidis G, Lonjon I, Castera L, Dhumeaux D. Antiviral action of ribavirin in chronic hepatitis C. Gastroenterology 2004; 126:703-714. (Pubitemid 38298318)
46. Parker WB. Metabolism and antiviral activity of ribavirin. Virus Res 2005;107:165-171. (Pubitemid 40093089)
47. Chevaliez S, Brillet R, Lázaro E, Hézode C, Pawlotsky JM. Analysis of ribavirin mutagenicity in human hepatitis C virus infection. J Virol 2007;81:7732-7741. (Pubitemid 47047859)
48. Feld JJ, Nanda S, Huang Y, Chen W, Cam M, Pusek SN, Schweigler LM, Theodore D, Zacks SL, Liang TJ, Fried MW. Hepatic gene expression during treatment with peginterferon and ribavirin: Identifying molecular pathways for treatment response. Hepatology 2007;46:1548-1563. (Pubitemid 350155537)
49. Liu WL, Su WC, Cheng CW, Hwang LH, Wang CC, Chen HL, Chen DS, Lai MY. Ribavirin up-regulates the activity of double-stranded RNA-activated protein kinase and enhances the action of interferon-alpha against hepatitis C virus. J Infect Dis 2007;196:425-434. (Pubitemid 47093893)
50. Perelson AS, Layden TJ. Ribavirin: Is it a mutagen for hepatitis C virus? Gastroenterology 2007;132:2050-2052.
51. Hofmann WP, Polta A, Herrmann E, Mihm U, Kronenberger B, Sonntag T, Lohmann V, Schönberger B, Zeuzem S, Sarrazin C. Mutagenic effect of ribavirin on hepatitis C nonstructural 5B quasispecies in vitro and during antiviral therapy. Gastroenteriology 2007;132:921-930. (Pubitemid 46440857)
52. Lutchman G, Danehower S, Song BC, Liang TJ, Hoofnagle JH, Thomson M, Ghany MG. Mutation rate of the hepatitis C virus NS5B in patients undergoing treatment with ribavirin monotherapy. Gastroenterology 2007;132:1757-1766. (Pubitemid 46677946)
53. Dixit NM, Layden-Almer JE, Layden TJ, Perelson AS. Modelling how ribavirin improves interferon response rates in hepatitis C virus infection. Nature 2004;432:922-924. (Pubitemid 40037156)
54. De Clercq E. ASPET Otto Krayer Award Lecture. Molecular targets for antiviral agents. J Pharmacol Exp Ther 2001;297:1-10. (Pubitemid 32242557)
55. De Clercq E. John Montgomery's legacy: Carbocyclic adenosine analogues as SAH hydrolase inhibitors with broad-spectrum antiviral activity. Nucleosides Nucleotides Nucleic Acids 2005;24:1395-1415. (Pubitemid 41831807)
56. De Clercq E. S-adenosylhomocysteine hydrolase inhibitors as broad-spectrum antiviral agents. Biochem Pharmacol 1987;36:2567-2575.
57. De Clercq E, Descamps J, De Somer P, Holý A. (S)-9-(2,3- Dihydroxypropyl)adenine: An aliphatic nucleoside analog with broad-spectrum antiviral activity. Science 1978;200:563-565.
58. Montgomery JA, Clayton SJ, Thomas HJ, Shannon WM, Arnett G, Bodner AJ, Kion IK, Cantoni GL, Chiang PK. Carbocyclic analogue of 3-deazaadenosine: A novel antiviral agent using S-adenosylhomocysteine hydrolase as a pharmacological target. J Med Chem 1982;25:626-629. (Pubitemid 13238093)
59. Borchardt RT, Keller BT, Patel-Thombre U. Neplanocin A. A potent inhibitor of S-adenosylhomocysteine hydrolase and of vaccinia virus multiplication in mouse L929 cells. J Biol Chem 1984;259:4353-4358. (Pubitemid 14127799)
60. De Clercq E, Cools M. Antiviral potency of adenosine analogues: Correlation with inhibition of S-adenosylhomocysteine hydrolase. Biochem Biophys Res Commun 1985;129:306-311. (Pubitemid 15060081)
61. Cools M, De Clercq E. Influence of S-adenosylhomocysteine hydrolase inhibitors on S-adenosylhomocysteine and S-adenosylmethionine pool levels in L929 cells. Biochem Pharmacol 1989;38:1061-1067.
62. De Clercq E, Cools M, Balzarini J, Marquez VE, Borcherding DR, Borchardt RT, Drach JC, Kitaoka S, Konno T. Broad-spectrum antiviral activities of neplanocin A, 3-deazaneplanocin A, and their 5′-nor derivatives. Antimicrob Agents Chemother 1989;33:1291-1297. (Pubitemid 19191974)
63. Tseng CK, Marquez VE, Fuller RW, Goldstein BM, Haines DR, McPherson H, Parsons JL, Shannon WM, Arnett G, Hollingshead M, Driscoll JS. Synthesis of 3-deazaneplanocin A, a powerful inhibitor of S-adenosylhomocysteine hydrolase with potent and selective in vitro and in vivo antiviral activities. J Med Chem 1989;32:1442-1446. (Pubitemid 19205346)
64. Bray M, Driscoll J, Huggins JW. Treatment of lethal Ebola virus infection in mice with a single dose of an S-adenosyl-L-homocysteine hydrolase inhibitor. Antiviral Res 2000;45:135-147. (Pubitemid 30156782)
65. Bray M, Raymond JL, Geisbert T, Baker RO. 3-Deazaneplanocin A induces massively increased interferon-alpha production in Ebola virus-infected mice. Antiviral Res 2002;55:151-159. (Pubitemid 34655650)
66. De Fazio G, Alba AP, Vicente M, De Clercq E. Antiviral activity of S-adenosylhomocysteine hydrolase inhibitors against plant viruses. Antiviral Res 1990;13:219-226. (Pubitemid 20185343)
67. Shuto S, Minakawa N, Niizuma S, Kim HS, Wataya Y, Matsuda A. New neplanocin analogues 12 alternative synthesis and antimalarial effect of (60R)-6′-C-methylneplanocin A, a potent AdoHcy hydrolase inhibitor. J Med Chem 2002;45:748-751. (Pubitemid 34145722)
68. Cai S, Li QS, Borchardt RT, Kuczera K, Schowen RL. The antiviral drug ribavirin is a selective inhibitor of S-adenosyl-L-homocysteine hydrolase from Trypanosoma cruzi. Bioorg Med Chem 2007;15:7281-7287. (Pubitemid 47539149)
69. Davies WL, Grunert RR, Haff RF, McGahen JW, Neumayer EM, Paulshock M, Watts JC, Wood TR, Hermann EC, Hoffmann CE. Antiviral activity of 1-adamantanamine (amantadine). Science 1964;144:862-863.
70. Shuck K, Lamb RA, Pinto LH. Analysis of the pore structure of the influenza A virus M(2) ion channel by the substituted-cysteine accessibility method. J Virol 2000;74:7755-7761.
71. Sansom MS, Kerr ID. Influenza virus M2 protein: A molecular modelling study of the ion channel. Protein Eng 1993;6:65-74. (Pubitemid 23048942)
72. De Clercq E. Antiviral agents active against influenza A viruses. Nat Rev Drug Discov 2006;5:1015-1025. (Pubitemid 44835128)
73. Bright RA, Shay DK, Shu B, Cox NJ, Klimov AI. Adamantane resistance among influenza A viruses isolated early during the 2005-2006 influenza season in the United States. J Am Med Assoc 2006;295:891-894.
74. Bright RA, Medina MJ, Xu X, Perez-Oronoz G, Wallis TR, Davis XM, Povinelli L, Cox NJ, Klimov AI. Incidence of adamantane resistance among influenza A (H3N2) viruses isolated worldwide from 1994 to 2005: A cause for concern. Lancet 2005;366:1175-1181.
75. He G, Qiao J, Dong C, He C, Zhao L, Tian Y. Amantadine-resistance among H5N1 avian influenza viruses isolated in Northern China. Antiviral Res 2008;77:72-76.
76. Weinstock DM, Zuccotti G. Adamantane resistance in influenza A. J Am Med Assoc 2006;295: 934-936. (Pubitemid 43295829)
77. Kolocouris N, Foscolos GB, Kolocouris A, Marakos P, Pouli N, Fytas G, Ikeda S, De Clercq E. Synthesis and antiviral activity evaluation of some aminoadamantane derivatives. J Med Chem 1994;37:2896-2902. (Pubitemid 24297806)
78. Stamatiou G, Foscolos GB, Fytas G, Kolocouris A, Kolocouris N, Pannecouque C, Witvrouw M, Padalko E, Neyts J, De Clercq E. Heterocyclic rimantadine analogues with antiviral activity. Bioorg Med Chem 2003;11:5485-5492. (Pubitemid 37464675)
79. Stamatiou G, Kolocouris A, Kolocouris N, Fytas G, Foscolos GB, Neyts J, De Clercq E. Novel 3-(2-adamantyl)pyrrolidines with potent activity against influenza A virus-identification of aminoadamantane derivatives bearing two pharmacophoric amine groups. Bioorg Med Chem Lett 2001;11:2137-2142. (Pubitemid 32763017)
80. Kolocouris A, Tataridis D, Fytas G, Mavromoustakos T, Foscolos GB, Kolocouris N, De Clercq E. Synthesis of 2-(2-adamantyl)piperidines and structure anti-influenza virus A activity relationship study using a combination of NMR spectroscopy and molecular modeling. Bioorg Med Chem Lett 1999;9:3465-3470.
81. Kolocouris N, Kolocouris A, Foscolos GB, Fytas G, Neyts J, Padalko E, Balzarini J, Snoeck R, Andrei G, De Clercq E. Synthesis and antiviral activity evaluation of some new aminoadamantane derivatives. 2. J Med Chem 1996;39:3307-3318. (Pubitemid 26322856)
82. Zoidis G, Fytas C, Papanastasiou I, Foscolos GB, Fytas G, Padalko E, De Clercq E, Naesens L, Neyts J, Kolocouris N. Heterocyclic rimantadine analogues with antiviral therapy. Bioorg Med Chem 2006;14:3341-3348.
83. Stylianakis I, Kolocouris A, Kolocouris N, Fytas G, Foscolos GB, Padalko E, Neyts J, De Clercq E. Spiro[pyrrolidine-2,2′-adamantanes]: Synthesis, anti-influenza virus activity and conformational properties. Bioorg Med Chem Lett 2003;13:1699-1703.
84. Tanner JA, Zheng BJ, Zhou J, Watt RM, Jiang JQ, Wong KL, Lin YP, Lu LY, He ML, Kung HF, Kessel AJ, Huang JD. The adamantane-derived bananins are potent inhibitors of the helicase activities and replication of SARS coronavirus. Chem Biol 2005;12:303-311. (Pubitemid 40406277)
85. Zoidis G, Kolocouris N, Foscolos GB, Kolocouris A, Fytas G, Karayannis P, Padalko E, Neyts J, De Clercq E. Are the 2-isomers of the drug rimantadine active anti-influenza A agents? Antiviral Chem Chemother 2003;14:153-164.
86. Lagoja I, De Clercq E. Anti-influenza virus agents: Synthesis and mode of action. Med Res Rev 2008;28:1-38. (Pubitemid 350274960)
87. Kolocouris N, Zoidis G, Foscolos GB, Fytas G, Prathalingham SR, Kelly JM, Naesens L, De Clercq E. Design and synthesis of bioactive adamantane spiro heterocycles. Bioorg Med Chem Lett 2007;17:4358-4362. (Pubitemid 47021378)
88. Zoidis G, Tsotinis A, Kolocouris N, Kelly JM, Prathalingam SR, Naesens L, De Clercq E. Design and synthesis of bioactive 1,2-annulated adamantane derivatives. Org Biomol Chem 2008;6: 3177-3185.
89. Thuluvath PJ, Maheshwari A, Mehdi J, Fairbanks KD, Wu LL, Gelrud LG, Ryan MJ, Anania FA, Lobis IF, Black M. Randomised, double blind, placebo controlled trial of interferon, ribavirin, and amantadine versus interferon, ribavirin, and placebo in treatment naïve patients with chronic hepatitis C. Gut 2004;53:130-135. (Pubitemid 38083021)
90. Angelico M, Cepparulo M, Angelico F, Francioso S, Barlattani A, Di Candilo F, Della Vecchia R, Demelia L, De Sanctis G, Gentile S, Grieco A, Parruti G, Sabusco G, Tarquini L, Tosti A, Zaru S. A randomized controlled trial of amantadine plus interferon-a2a vs interferona2a alone in naïve patients with chronic hepatitis C randomized according to the early virological response to interferon-a2a monotherapy. Aliment Pharmacol Ther 2004;19:339-347. (Pubitemid 38253509)
91. Mangia A, Ricci GL, Persico M, Minerva N, Carretta V, Bacca D, Cela M, Piattelli M, Annese M, Maio G, Conte D, Guadagnino V, Pazienza V, Festi D, Spirito F, Andriulli A. A randomized controlled trial of pegylated interferon a2a (40 KD) or interferon α-2a plus ribavirin and amantadine vs interferon α-2a and ribavirin in treatment-näve patients with chronic hepatitis C. J Viral Hepat 2005;12:292-299. (Pubitemid 40638037)
92. Ferenci P, Formann E, Laferl H, Gschwantler M, Hackl F, Brunner H, Hubmann R, Datz C, Stauber R, Steindl-Munda P, Kessler HH, Klingler A, Gangl A. Randomized, double-blind, placebo-controlled study of peginterferon a2a (40KD) plus ribavirin with or without amantadine in treatment-näve patients with chronic hepatitis C genotype 1 infection. J Hepatol 2006;44: 275-282. (Pubitemid 43069208)
93. Ciancio A, Picciotto A, Giordanino C, Smedile A, Tabone M, Manca A, Marenco G, Garbagnoli P, Andreoni M, Cariti G, Calleri G, Sartori M, Cusumano S, Grasso A, Rizzi R, Gallo M, Basso M, Anselmo M, Percario G, Ciccone G, Rizzetto M, Saracco G. A randomized trial of pegylated interferon-a2a plus ribavirin with or without amantadine in the re-treatment of patients with chronic hepatitis C not responding to standard interferon and ribavirin. Aliment Pharmacol Ther 2006;24:1079-1086. (Pubitemid 44386533)
94. Angelico C, Koehler-Horst B, Piccolo P, Angelico F, Gentile S, Francioso S, Tarquini P, Vecchia RD, Ponti L, Pilleri G, Barlattani A, Grieco A, Soccorsi F, Guarascio P, Demelia L, Sorbello O, Rossi Z, Forlini G, Zaru S, Bandiera F. Peginterferon α-2a and ribavirin versus peginterferon α-2a monotherapy in early virological responders and peginterferon α-2a and ribavirin versus peginterferon α-2a, ribavirin and amantadine triple therapy in early virological nonresponders: The SMIEC II trial in näve patients with chronic hepatitis C. Eur J Gastroenterol Hepatol 2008;20:680-687.
95. von Wagner M, Hofmann WP, Teuber G, Berg T, Goeser T, Spengler U, Hinrichsen H, Weidenbach H, Gerken G, Manns M, Buggisch P, Herrmann E, Zeuzem S. Placebo-controlled trial of 400mg amantadine combined with peginterferon a2a and ribavirin for 48 weeks in chronic hepatitis C virus-1 infection. Hepatology 2008;48:1404-1411.
96. Prusoff WH. Synthesis and biological activities of iododeoxyuridine, an analog of thymidine. Biochim Biophys Acta 1959;32:295-296.
97. Kaufman HE. Clinical cure of herpes simplex keratitis by 5-iodo-2′-deoxyuridine. Proc Soc Exp Biol Med 1962;109:251-253.
98. Kaufman HE, Heidelberger C. Therapeutic antiviral action of 5-trifluoromethyl-2′-deoxyuridine in herpes simplex keratitis. Science 1964;145:585-586.
99. Field HJ, De Clercq E. Antiviral chemistry and chemotherapy's current antiviral agents FactFile (2nd edition): DNA viruses. Antiviral Chem Chemother 2008;19:51-62.
100. Boston Interhospital Virus Study Group and the NIAID-Sponsored Cooperative Antiviral Clinical Study. Failure of high dose 5-iodo-2′- deoxyuridine in the therapy of herpes simplex virus encephalitis. Evidence of unacceptable toxicity. N Engl J Med 1975;292:599-603.
101. Spruance SL, Stewart JC, Freeman DJ, Brightman VJ, Cox JL, Wenerstrom G, McKeough MB, Rowe NH. Early application of topical 15% idoxuridine in dimethyl sulfoxide shortens the course of herpes simplex labialis: A multicenter placebo-controlled trial. J Infect Dis 1990;161: 191-197. (Pubitemid 20056645)
102. De Clercq E. Antiviral and antitumor activities of 5-substituted 2′-deoxyuridines. Methods Find Exp Clin Pharmacol 1980;2:253-267. (Pubitemid 11254698)
103. De Clercq E. The antiviral spectrum of (E)-5-(2-bromovinyl)-2′- deoxyuridine. J Antimicrob Chemother 1984;14:85-95.
104. Maudgal PC, De Clercq E, Descamps J, Missotten L, De Somer P, Busson R, Vanderhaeghe H, Verhelst G, Walker RT, Jones AS. (E)-5-(2-bromovinyl)-2′- deoxyuridine in the treatment of experimental herpes simplex keratitis. Antimicrob Agents Chemother 1980;17:8-12. (Pubitemid 10215574)
105. Maudgal PC, De Clercq E, Descamps J, Missotten L, Wijnhoven J. Experimental stroma herpes simplex keratitis. Influence of treatment with topical bromovinyldeoxyuridine and trifluridine. Arch Opthalmol 1982;100:653-656.
106. Maudgal PC, Uyttebroeck W, De Clercq E, Missotten L. Oral and topical treatment of experimental herpes simplex iritis with bromovinyldeoxyuridine. Arch Ophthalmol 1982;100:1337-1340.
107. Maudgal PC, De Clercq E. Evaluation of bromovinyldeoxyuridine-related compounds in the treatment of experimental herpes simplex keratitis. Arch Ophthalmol 1985;103:1393-1397. (Pubitemid 15230635)
108. Maudgal PC, De Clercq E. Bromovinyldeoxyuridine treatment of herpetic keratitis clinically resistant to other antiviral agents. Curr Eye Res 1991;10:193-199.
109. Elion GB, Furman PA, Fyfe JA, de Miranda P, Beauchamp L, Schaeffer HJ. Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl) guanine. Proc Natl Acad Sci USA 1977; 74:5716-5720.
110. Schaeffer HJ, Beauchamp L, de Miranda P, Elion GB, Bauer DJ, Collins P. 9-(2-hydroxyethoxymethyl) guanine activity against viruses of the herpes group. Nature 1978;272: 583-585. (Pubitemid 8305178)
111. Privat de Garilhe M, de Rudder J. Effet de deux nucléosides de l'arabinose sur la multiplication des virus de l'herpè s et de la vaccine en culture cellulaire. C R Acad Sci (Paris) 1964;259: 2725-2728.
112. Schabel Jr FM. The antiviral activity of 9-beta-D-arabinofuranosyladenine (Ara-A). Chemotherapy 1968;13:321-338.
113. Whitley RJ, Ch'ien LT, Dolin R, Galasso GJ, Alford Jr CA. Adenine arabinoside therapy of herpes zoster in the immunosuppressed. NIAID collaborative antiviral study. N Engl J Med 1976;294:1193-1199.
114. Whitley RJ, Soong SJ, Dolin R, Galasso GJ, Ch'ien LT, Alford CA. Adenine arabinoside therapy of biopsy-proved herpes simplex encephalitis. National Institute of Allergy and Infectious Diseases collaborative antiviral study. N Engl J Med 1977;297:289-294. (Pubitemid 8161781)
115. Whitley RJ, Arvin A, Prober C, Burchett S, Corey L, Powell D, Plotkin S, Starr S, Alford C, Connor J. A controlled trial comparing vidarabine with acyclovir in neonatal herpes simplex virus infection. N Engl J Med 1991;324:444-449.
116. Field HJ, De Clercq E. Antiviral drugs-a short history of their discovery and development. Microbiol Today 2004;31:58-61.
117. De Clercq E, Andrei G, Snoeck R, De Bolle L, Naesens L, Degrève B, Balzarini J, Zhang Y, Schols D, Leyssen P, Ying C, Neyts J. Acyclic/carbocyclic guanosine analogues as anti-herpesvirus agents. Nucleosides Nucleotides Nucleic Acids 2001;20:271-285. (Pubitemid 32821789)
118. De Clercq E. Antiviral drugs in current clinical use. J Clin Virol 2004;30:115-133. (Pubitemid 38582018)
119. De Clercq E, Field HJ. Antiviral prodrugs-the development of successful prodrug strategies for antiviral chemotherapy. Br J Pharmacol 2006;147:1-11. (Pubitemid 43069091)
120. Larsson A, Stenberg K, Ericson AC, Haglund U, Yisak WA, Johansson NG, Öberg B, Datema R. Mode of action, toxicity, pharmacokinetics, and efficacy of some new antiherpesvirus guanosine analogs related to buciclovir. Antimicrob Agents Chemother 1986;30:598-605. (Pubitemid 16030706)
121. Soike KF, Bohm R, Huang JL, Öberg B. Efficacy of (-)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine in African green monkeys infected with simian varicella virus. Antimicrob Agents Chemother 1993;37:1370-1372. (Pubitemid 23166743)
122. Descamps J, De Clercq E. Broad-spectrum antiviral activity of pyrazofurin (pyrazomycin). In: Siegenthaler W, Lüthy R, editors. Current Chemotherapy (Proceedings of the Tenth International Congress of Chemotherapy, Zürich, Switzerland; 18-23 September 1977). Washington, DC: American Society for Microbiology; 1978. pp 354-357.
123. Andrei G, De Clercq E. Molecular approaches for the treatment of hemorrhagic fever virus infections. Antiviral Res 1993;22:45-75. (Pubitemid 23256719)
124. Shigeta S, Konno K, Yokota T, Nakamura K, De Clercq E. Comparative activities of several nucleoside analogs against influenza A, B, and C viruses in vitro. Antimicrob Agents Chemother 1988;32:906-911. (Pubitemid 18141026)
125. Neyts J, Meerbach A, McKenna P, De Clercq E. Use of the yellow fever virus vaccine strain 17D for the study of strategies for the treatment of yellow fever virus infections. Antiviral Res 1996;30:125-132. (Pubitemid 26178132)
126. Kawana F, Shigeta S, Hosoya M, Suzuki H, De Clercq E. Inhibitory effects of antiviral compounds on respiratory syncytial virus replication in vitro. Antimicrob Agents Chemother 1987;31:1225-1230. (Pubitemid 17157604)
127. Hosoya M, Shigeta S, Nakamura K, De Clercq E. Inhibitory effect of selected antiviral compounds on measles (SSPE) virus replication in vitro. Antiviral Res 1989;12:87-97. (Pubitemid 19236889)
128. Georges-Courbot MC, Contamin H, Faure C, Loth P, Baize S, Leyssen P, Neyts J, Deubel V. Poly(I)-poly(C12U) but not ribavirin prevents death in a hamster model of Nipah virus infection. Antimicrob Agents Chemother 2006;50:1768-1772.
129. Rada B, Dragún M. Antiviral action and selectivity of 6-azauridine. Ann NY Acad Sci 1977;284:410-417.
130. Shannon WM, Arnett G, Westbrook L, Shealy YF, O'Dell CA, Brockman RW. Evaluation of carbodine, the carbocyclic analog of cytidine, and related carbocyclic analogs of pyrimidine nucleosides for antiviral activity against human influenza Type A viruses. Antimicrob Agents Chemother 1981;20:769-776. (Pubitemid 12188193)
131. De Clercq E, Bernaerts R, Shealy YF, Montgomery JA. Broad-spectrum antiviral activity of carbodine, the carbocyclic analogue of cytidine. Biochem Pharmacol 1990;39:319-325. (Pubitemid 20025621)
132. Marquez VE, Lim MI, Treanor SP, Plowman J, Priest MA, Markovac A, Khan MS, Kaskar B, Driscoll JS. Cyclopentenylcytosine. A carbocyclic nucleoside with antitumor and antiviral properties. J Med Chem 1988;31:1687-1694. (Pubitemid 18214392)
133. Julander JG, Bowen RA, Rao JR, Day C, Shafer K, Smee DF, Morrey JD, Chu CK. Treatment of Venezuelan equine encephalitis virus infection with (-)-carbodine. Antiviral Res 2008;80:309-315.
134. Schimmel KJ, Nijmeijer BA, van SchieML, Falkenburg JH, Guchelaar HJ. Limited antitumor-effect associated with toxicity of the experimental cytotoxic drug cyclopentenyl cytosine in NOD/scid mice with acute lymphoblastic leukemia. Leuk Res 2007;31:1545-1551. (Pubitemid 47632794)
135. Langley DB, Shojaei M, Chan C, Lok HC, Mackay JP, Traut TW, Guss JM, Christopherson RI. Structure and inhibition of orotidine 5'-monophosphate decarboxylase from Plasmodium falciparum. Biochemistry 2008;47:3842-3854.
136. De Clercq E. The design of drugs for HIV and HCV. Nature Rev Drug Discov 2007;6:1001-1018. (Pubitemid 350213865)
137. Domagk G, Behnisch R, Mietzch F, Schmidt H. Über eine neue, gegen Tuberkelbazillen in vitro wirksame Verbindungsklasse. Naturwissenschaften 1946;10:315.
138. Hamre D, Brownlee KA, Donovick R. Studies on the chemotherapy of vaccinia virus. II. The activity of some thiosemicarbazones. J Immunol 1951;67:305-312.
139. Bauer DJ. The antiviral and synergic actions of isatin thiosemicarbazone and certain phenoxypyrimidines in vaccinia infection in mice. Br J Exp Pathol 1955;36:105-114.
140. Bauer DJ, St Vincent L, Kempe CH, Downie AW. Prophylactic treatment of
141. Fenner FJ, White DO. Medical virology. New York, NY: Academic Press, Inc; 1970. 190p.
142. De Clercq E. Vaccinia virus inhibitors as a paradigm for the chemotherapy of poxvirus infections. Clin Microbiol Rev 2001;14:382-397. (Pubitemid 32294676)
143. De Clercq E. Cidofovir in the treatment of poxvirus infections. Antiviral Res 2002;55:1-13. (Pubitemid 34655638)
144. Neyts J, Leyssen P, Verbeken E, De Clercq E. Efficacy of cidofovir in a murine model of disseminated progressive vaccinia. Antimicrob Agents Chemother 2004;48:2267-2273. (Pubitemid 38691628)
145. Quenelle DC, Collins DJ, Herrod BP, Keith KA, Trahan J, Beadle JR, Hostetler KY, Kern ER. Effect of oral treatment with hexadecyloxypropyl-[(S)-9- (3-hydroxy-2-phosphonylmethoxypropyl)adenine] [(S)-HPMPA] or octadecyloxy-ethyl-(S)-HPMPA on cowpox or vaccinia virus infections in mice. Antimicrob Agents Chemother 2007;51:3940-3947. (Pubitemid 350057792)
146. Beadle JR, Wan WB, Ciesla SL, Keith KA, Hartline C, Kern ER, Hostetler KY. Synthesis and antiviral evaluation of alkoxyalkyl derivatives of 9-(S)-(3-hydroxy-2-phosphonomethoxypropyl)adenine against cytomegalovirus and orthopoxviruses. J Med Chem 2006;49:2010-2015.
147. De Clercq E. Emerging antiviral drugs. Expert Opin Emerg Drugs 2008;13:393-416.
148. Geerinck K, Lukito G, Snoeck R, De Vos R, De Clercq E, Vanrenterghem Y, Degreef H, Maes B. A case of human orf in an immunocompromised patient treated successfully with cidofovir cream. J Med Virol 2001;64:543-549. (Pubitemid 32613744)
149. Fery-Blanco C, Pelletier F, Humbert P, Aubin F. Disseminated molluscum contagiosum during topical treatment of atopic dermatitis with tacrolimus: Efficacy of cidofovir. Ann Dermatol Venereol 2007;134:457-459. (Pubitemid 46797777)
150. Bolken TC, Hruby DE. Discovery and development of antiviral drugs for biodefense: Experience of a small biotechnology company. Antiviral Res 2008;77:1-5.
151. Bailey TR, Rippin SR, Opsitnick E, Burns CJ, Pevear DC, Collett MS, Rhodes G, Tohan S, Huggins JW, Baker RO, Kern ER, Keith KA, Dai D, Yang G, Hruby D, Jordan R. N-(3,3a,4,4a,5,5a,6,6a-Octahydro-1,3-dioxo-4,6-ethenocycloprop[f]- isoindol-2-(1H)-yl)carboxamides: Identification of novel orthopoxvirus egress inhibitors. J Med Chem 2007;50:1442-1444.
152. Yang G, Pevear DC, Davies MH, Collett MS, Bailey T, Rippen S, Barone L, Burns C, Rhodes G, Tohan S, Huggins JW, Baker RO, Buller RL, Touchette E, Waller K, Schriewer J, Neyts J, De Clercq E, Jones K, Hruby D, Jordan R. An orally bioavailable antipoxvirus compound (ST-246) inhibits extracellular virus formation and protects mice from lethal orthopoxvirus challenge. J Virol 2005;79:13139-13149. (Pubitemid 41433232)
153. Duraffour S, Snoeck R, De Vos R, van Den Oord JJ, Crance J-M, Garin D, Hruby DE, Jordan R, De Clercq E, Andrei G. Activity of the anti-orthopoxvirus compound ST-246 against vaccinia, cowpox and camelpox viruses in cell monolayers and organotypic raft cultures. Antivir Ther 2007;12:1205-1216.
154. Quenelle DC, Buller RML, Parker S, Keith KA, Hruby DE, Jordan R, Kern ER. Efficacy of delayed treatment with ST-246 given orally against systemic orthopoxvirus infections in mice. Antimicrob Agents Chemother 2007;51:689-695. (Pubitemid 46185291)
155. Sbrana E, Jordan R, Hruby DE, Mateo RI, Xiao SY, Siirin M, Newman PC, Da Rosa AP, Tesh RB. Efficacy of the antipoxvirus compound ST-246 for treatment of severe orthopoxvirus infection. Am J Trop Med Hyg 2007;76:768-773. (Pubitemid 351627722)
156. Nalca A, Hatkin JM, Garza NL, Nichols DK, Norris SW, Hruby DE, Jordan R. Evaluation of orally delivered ST-246 as postexposure prophylactic and antiviral therapeutic in an aerosolized rabbitpox rabbit model. Antiviral Res 2008;79:121-127.
157. Grosenbach DW, Jordan R, King DS, Berhanu A, Warren TK, Kirkwood-Watts DL, Tyavanagimatt S, Tan Y, Wilson RL, Jones KF, Hruby DE. Immune responses to the smallpox vaccine given in combination with ST-246, a small-molecule inhibitor of poxvirus dissemination. Vaccine 2008;26:933-946.
158. Quenelle DC, Prichard MN, Keith KA, Hruby DE, Jordan R, Painter GR, Robertson A, Kern ER. Synergistic efficacy of the combination of ST-246 with CMX001 against orthopoxviruses. Antimicrob Agents Chemother 2007;51:4118-4124. (Pubitemid 350057813)
159. Jordan R, Tien D, Bolken TC, Jones KF, Tyavanagimatt SR, Strasser J, Frimm A, Corrado ML, Strome PG, Hruby DE. Single-dose safety and pharmacokinetics of ST-246, a novel orthopoxvirus egress inhibitor. Antimicrob Agents Chemother 2008;52:1721-1727.
160. Kaiser J. A tame virus runs amok. Science 2007;316:1418-1419.
161. Vora S, Damon I, Fulginiti V, Weber SG, Kahana M, Stein SL, Gerber SI, Garcia-Houchins S, Lederman E, Hruby D, Collins L, Scott D, Thompson K, Barson JV, Regnery R, Hughes C, Daum RS, Li Y, Zhao H, Smith S, Braden Z, Karem K, Olson V, Davidson W, Trindade G, Bolken T, Jordan R, Tien D, Marcinak J. Severe eczema vaccinatum in a household contact of a smallpox vaccinee. Clin Infect Dis 2008;46:1555-1561. (Pubitemid 351706737)
162. Pauwels R, Andries K, Desmyter J, Schols D, Kukla MJ, Breslin HJ, Raeymaeckers A, Van Gelder J, Woestenborghs R, Heykants J, Schellekens K, Janssen MAC, De Clercq E, Janssen PAJ. Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives. Nature 1990;343:470-474. (Pubitemid 120028562)
163. Kukla MJ, Breslin HJ, Pauwels R, Fedde CL, Miranda M, Scott MK, Sherrill RG, Raeymaekers A, Van Gelder J, Andries K, Janssen MAC, De Clercq E, Janssen PAJ. Synthesis and anti-HIV-1 activity of 4,5,6,7-tetrahydro-5-methylimidazo[4, 5,1-jk][1,4]benzodiazepin-2(1H)-one (TIBO) derivatives. J Med Chem 1991;34:746-751.
164. Kukla MJ, Breslin HJ, Diamond CJ, Grous PP, Ho CY, Miranda M, Rodgers JD, Sherrill RG, De Clercq E, Pauwels R, Andries K, Moens LJ, Janssen MAC, Janssen PAJ. Synthesis and anti-HIV-1 activity of 4,5,6,7-tetrahydro-5-methyl-imidazo[4, 5,1-jk][1,4]benzodiazepin-2(1H)-one (TIBO) derivatives. J Med Chem 1991;34:3187-3197.
165. Pauwels R, Andries K, Debyser Z, Van Daele P, Schols D, Stoffels P, De Vreese K, Woestenborghs R, Vandamme A-M, Janssen CGM, Anné J, Cauwenbergh G, Desmyter J, Heykants J, Janssen MAC, De Clercq E, Janssen PAJ. Potent and highly selective human immunodeficiency virus type 1 (HIV-1) inhibition by a series of α-anilinophenylacetamide derivatives targeted at HIV-1 reverse transcriptase. Proc Natl Acad Sci USA 1993;90:1711-1715. (Pubitemid 23069926)
166. Ludovici DW, Kukla MJ, Grous PG, Krishnan S, Andries K, de Béthune M-P, Azijn H, Pauwels R, De Clercq E, Arnold E, Janssen PAJ. Evolution of anti-HIV drug candidates. Part 1: From α-anilinophenylacetamide (α-APA) to imidoyl thiourea (ITU). Bioorg Med Chem Lett 2001;11:2225-2228.
167. Ludovici DW, Kavash RW, Kukla MJ, Ho CY, Ye H, De Corte BL, Andries K, de Béthune MP, Azijn H, Pauwels R, Moereels HE, Heeres J, Koymans LM, de Jonge MR, Van Aken KJ, Daeyaert FF, Lewi PJ, Das K, Arnold E, Janssen PA. Evolution of anti-HIV drug candidates. Part 2: Diaryltriazine (DATA) analogues. Bioorg Med Chem Lett 2001;11:2229-2234.
168. Ludovici DW, De Corte BL, Kukla MJ, Ye H, Ho CY, Lichtenstein MA, Kavash RW, Andries K, de Béthune MP, Azijn H, Pauwels R, Lewi PJ, Heeres J, Koymans LM, de Jonge MR, Van Aken KJ, Daeyaert FF, Das K, Arnold E, Janssen PA. Evolution of anti-HIV drug candidates. Part 3: Diarylpyrimidine (DAPY) analogues. Bioorg Med Chem Lett 2001;11:2235-2239.
169. Andries K, Azijn H, Thielemans T, Ludovici D, Kukla M, Heeres J, Janssen P, De Corte B, Vingerhoets J, Pauwels R, de Béthune MP. TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1. Antimicrob Agents Chemother 2004;48:4680-4686. (Pubitemid 39577672)
170. Janssen PA, Lewi PJ, Arnold E, Daeyaert F, de Jonge M, Heeres J, Koymans L, Vinkers M, Guillemont J, Pasquier E, Kukla M, Ludovici D, Andries K, de Béthune MP, Pauwels R, Das K, Clark Jr AD, Frenkel YV, Hughes SH, Medaer B, De Knaep F, Bohets H, De Clerck F, Lampo A, Williams P, Stoffels P. In search of a novel anti-HIV drug: Multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino] -benzonitrile (R278474, rilpivirine). J Med Chem 2005;48:1901-1909.
171. van Roey J, von Schoen-Angerer T, Ford N, Calmy A. How developing world concerns need to be part of drug development plans: A case study of four emerging antiretrovirals. Drug Discov Today 2008;13:601-605.
172. Mordant C, Schmitt B, Pasquier E, Demestre C, Queguiner L, Masungi C, Peeters A, Smeulders L, Bettens E, Hertogs K, Heeres J, Lewi P, Guillemont J. Synthesis of novel diarylpyrimidine analogues of TMC278 and their antiviral activity against HIV-1 wild-type and mutant strains. Eur J Med Chem 2007;42:567-579. (Pubitemid 46729579)
173. Heeres J, Lewi PJ. The medicinal chemistry of the DATA and DAPY series of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Adv Antiviral Drug Des 2007;5: 213-242.
174. van 't Klooster G, Verloes R, Baert L, van Velsen F, Bouche MP, Spittaels K, Leempoels J, Williams P, Kraus G, Wigerinck P. Long-acting TMC278, a parenteral depot formulation delivering therapeutic NNRTI concentrations in preclinical and clinical settings. Abstracts of the 15th conference on retroviruses and opportunistic infections, Vol.134, Boston, MA, USA; 3-6 February 2008.
175. Ding J, Das K, Moereels H, Koymans L, Andries K, Janssen PA, Hughes SH, Arnold E. Structure of HIV-1 RT/TIBO R 86183 complex reveals similarity in the binding of diverse nonnucleoside inhibitors. Nat Struct Biol 1995;2:407-415.
176. Fang C, Bauman JD, Das K, Remorino A, Arnold E, Hochstrasser RM. Two-dimensional infrared spectra reveal relaxation of the nonnucleoside inhibitor TMC278 complexed with HIV-1 reverse transcriptase. Proc Natl Acad Sci USA 2008;105:1472-1477. (Pubitemid 351346538)
177. Das K, Bauman JD, Clark Jr AD, Frenkel YV, Lewi PJ, Shatkin AJ, Hughes SH, Arnold E. High-resolution structures of HIV-1 reverse transcriptase/TMC278 complexes: Strategic flexibility explains potency against resistance mutations. Proc Natl Acad Sci USA 2008;105:1466-1471. (Pubitemid 351346537)
178. De Clercq E, Holý A, Rosenberg I, Sakuma T, Balzarini J, Maudgal PC. A novel selective broad-spectrum anti-DNA virus agent. Nature 1986;323:464-467. (Pubitemid 16026278)
179. De Clercq E. Therapeutic potential of phosphonylmethoxyalkylpurines and pyrimidines as antiviral agents. Drugs Exp Clin Res 1990;16:319-326.
180. De Clercq E. Broad-spectrum anti-DNA virus and anti-retrovirus activity of phosphonylmethoxyalkylpurines and pyrimidines. Biochem Pharmacol 1991;42:963-972.
181. Yokota T, Konno K, Chonan E, Mochizuki S, Kojima K, Shigeta S, De Clercq E. Comparative activities of several nucleoside analogs against duck hepatitis B virus in vitro. Antimicrob Agents Chemother 1990;34:1326-1330. (Pubitemid 20215768)
182. Yokota T, Mochizuki S, Konno K, Mori S, Shigeta S, De Clercq E. Phosphonylmethoxyalkyl derivatives of purine as inhibitors of human hepatitis B virus DNA synthesis. Nucleic Acids Symp Ser 1990;17-18.
183. Yokota T, Mochizuki S, Konno K, Mori S, Shigeta S, De Clercq E. Inhibitory effects of selected antiviral compounds on human hepatitis B virus DNA synthesis. Antimicrob Agents Chemother 1991;35:394-397.
184. Heijtink RA, de Wilde GA, Kruining J, Berk L, Balzarini J, De Clercq E, Holý A, Schalm SW. Inhibitory effect of 9-(2-phosphonylmethoxyethyl)- adenine (PMEA) on human and duck hepatitis B virus infection. Antiviral Res 1993;21:141-153. (Pubitemid 23150958)
185. Heijtink RA, Kruining J, de Wilde GA, Balzarini J, De Clercq E, Schalm SW. Inhibitory effects of acyclic nucleoside phosphonates on human hepatitis B virus and duck hepatitis B virus infections in tissue culture. Antimicrob Agents Chemother 1994;38:2180-2182. (Pubitemid 24278823)
186. Balzarini J, Holý A, Jindrich J, Naesens L, Snoeck R, Schols D, De Clercq E. Differential antiherpesvirus and antiretrovirus effects of the (S) and (R) enantiomers of acyclic nucleoside phosphonates: Potent and selective in vitro and in vivo antiretrovirus activities of (R)-9-(2- phosphonomethoxypropyl) -2,6-diaminopurine. Antimicrob Agents Chemother 1993;37:332-338. (Pubitemid 23046579)
187. Ying C, Van Pelt J, Yap SH, De Clercq E, Neyts J. Use of digoxigenin-labelled probes for the quantitation of HBV-DNA in antiviral drug evaluation. J Virol Methods 1999;81:155-158. (Pubitemid 29371782)
188. 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;7:79-83. (Pubitemid 30139856)
189. Ying C, De Clercq E, Nicholson W, Furman P, Neyts J. Inhibition of the replication of the DNA polymerase M550V mutation variant of human hepatitis B virus by adefovir, tenofovir, L-FMAU, DAPD, penciclovir and lobucavir. J Viral Hepat 2000;7:161-165. (Pubitemid 30177107)
190. Lada O, Benhamou Y, Cahour A, Katlama C, Poynard T, Thibault V. In vitro susceptibility of lamivudine-resistant hepatitis B virus to adefovir and tenofovir. Antivir Ther 2004;9:353-363.
191. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, Marcellin P, Lim SG, Goodman Z, Wulfsohn MS, Xiong S, Fry J, Brosgart CL. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med 2003;348:800-807. (Pubitemid 36245756)
192. Marcellin P, Chang TT, Lim SG, Tong MJ, Sievert W, Shiffman ML, Jeffers L, Goodman Z, Wulfsohn MS, Xiong S, Fry J, Brosgart CL. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 2003;348:808-816. (Pubitemid 36245757)
193. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, Marcellin P, Lim SG, Goodman Z, Ma J, Arterburn S, Xiong S, Currie G, Brosgart CL. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B. N Engl J Med 2005;352:2673-2681. (Pubitemid 41007822)
194. Delaney IVWE, Ray AS, Yang H, Qi X, Xiong S, Zhu Y,MillerMD. Intracellular metabolism and in vitro activity of tenofovir against hepatitis B virus. Antimicrob Agents Chemother 2006;50:2471-2477. (Pubitemid 43993188)
195. Qi X, Xiong S, Yang H, Miller M, Delaney IV WE. In vitro susceptibility of adefovir-associated hepatitis B virus polymerase mutations to other antiviral agents. Antivir Ther 2007;12:355-362.
196. Menne S, Cote PJ, Korba BE, Butler SD, George AL, Tochkov IA, Delaney IV WE, Xiong S, Gerin JL, Tennant BC. Antiviral effect of oral administration of tenofovir disoproxil fumarate in woodchucks with chronic woodchuck hepatitis virus infection. Antimicrob Agents Chemother 2005;49:2720-2728. (Pubitemid 40917584)
197. Menne S, Butler SD, George AL, Tochkov IA, Zhu Y, Xiong S, Gerin JL, Cote PJ, Tennant BC. Antiviral effects of lamivudine, emtricitabine, adefovir dipivoxil, and tenofovir disoproxil fumarate administered orally alone and in combination to woodchucks with chronic woodchuck hepatitis virus infection. Antimicrob Agents Chemother 2008;52:3617-3632.
198. Ristig MB, Crippin J, Aberg JA, Powderly WG, Lisker-Melman M, Kessels L, Tebas P. Tenofovir disoproxil fumarate therapy for chronic hepatitis B in human immunodeficiency virus/hepatitis B virus-coinfected individuals for whom interferon-alpha and lamivudine therapy have failed. J Infect Dis 2002;186:1844-1847. (Pubitemid 35463519)
199. Dore GJ, Cooper DA, Pozniak AL, DeJesus E, Zhong L, Miller MD, Lu B, Cheng AK. Efficacy of tenofovir disoproxil fumarate in antiretroviral therapy-naive and -experienced patients coinfected with HIV-1 and hepatitis B virus. J Infect Dis 2004;189:1185-1192. (Pubitemid 38457242)
200. Peters MG, Andersen J, Lynch P, Liu T, Alston-Smith B, Brosgart CL, Jacobson JM, Johnson VA, Pollard RB, Rooney JF, Sherman KE, Swindells S, Polsky B. Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127. Hepatology 2006;44:1110-1116. (Pubitemid 44748362)
201. van Bömmel F, Wünsche T, Mauss S, Reinke P, Bergk A, Schürmann D, Wiedenmann B, Berg T. Comparison of adefovir and tenofovir in the treatment of lamivudine-resistant hepatitis B virus infection. Hepatology 2004;40:1421-1425. (Pubitemid 39657017)
202. Kuo A, Dienstag JL, Chung RT. Tenofovir disoproxil fumarate for the treatment of lamivudine-resistant hepatitis B. Clin Gastroenterol Hepatol 2004;2:266-272. (Pubitemid 38293315)
203. Marcellin P, Buti M, Krastev Z, Germanidis G, Kaita KD, Kotzev I, Buggisch P, Weilert F, Trinh HN, Sorbel J, Anderson J, Mondou E, Rousseau F. A randomized, double-blind, comparison of tenofovir DF (TDF) versus adefovir dipivoxil (ADV) for the treatment of HBeAg-negative chronic hepatitis B (CHB): Study GS-US-174-0102. The 58th annual meeting of the American association for the study of liver diseases, Boston, MA; 2-6 November 2007. Oral presentation LB2.
204. Heathcote EJ, et al. The 58th annual meeting of the American association for the study of liver diseases, Boston, MA; 2-6 November 2007. Poster LB6.
205. Del Poggio P, Zaccanelli M, Oggionni M, Colombo S, Jamoletti C, Puhalo V. Low-dose tenofovir is more potent than adefovir and is effective in controlling HBV viremia in chronic HbeAg-negative hepatitis B. World J Gastroenterol 2007;13:4096-4099. (Pubitemid 47323163)
206. http://investors.gilead.com/.
207. Marcellin P, Heathcote EJ, Buti M, Gane E, de Man RA, Krastev Z, Germanidis G, Lee SS, Flisiak R, Kaita K, Manns M, Kotzev I, Tchernev K, Buggisch P, Weilert F, Kurdas OQ, Shiffman ML, Trinh H, Washington MK, Sorbel J, Anderson J, Snow-Lampart A, Mondou E, Quinn J, Rousseau F. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med 2008;359:2442-2455.