Case history: Acyclic nucleoside phosphonates: A key class of antiviral drugs

Nature Reviews Drug Discovery

Volumn 4, Issue 11, 2005, Pages 928-940

  De Clercq, Erik ^a   Holý, Antonín ^b  

^a REGA INSTITUTE FOR MEDICAL RESEARCH   (Belgium)

^b INSTITUTE OF ORGANIC CHEMISTRY AND BIOCHEMISTRY   (Czech Republic)

Author keywords

[No Author keywords available]

Indexed keywords

2',3' DIDEOXYNUCLEOSIDE DERIVATIVE; ABACAVIR; ABACAVIR PLUS LAMIVUDINE; ACICLOVIR; ADEFOVIR; ADEFOVIR DIPIVOXIL; AMPRENAVIR; ANTINEOPLASTIC AGENT; ANTIVIRUS AGENT; CIDOFOVIR; DIDANOSINE; EFAVIRENZ; EMIVIRINE; EMTRICITABINE; EMTRICITABINE PLUS TENOFOVIR DISOPROXIL; GANCICLOVIR; INDINAVIR; LAMIVUDINE; NELFINAVIR; NEVIRAPINE; NUCLEOSIDE DERIVATIVE; PENCICLOVIR; PHOSPHONIC ACID DERIVATIVE; RNA DIRECTED DNA POLYMERASE INHIBITOR; SAQUINAVIR; STAVUDINE; TENOFOVIR; TENOFOVIR DISOPROXIL; UNINDEXED DRUG; ZIDOVUDINE; NUCLEOSIDE;

ACQUIRED IMMUNE DEFICIENCY SYNDROME; ACUTE KIDNEY FAILURE; ADENOVIRUS; ANTIBIOTIC RESISTANCE; ANTINEOPLASTIC ACTIVITY; ANTIVIRAL ACTIVITY; CANCER; CLINICAL TRIAL; DISEASE MODEL; DNA VIRUS; DOSE RESPONSE; DRUG APPROVAL; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG HALF LIFE; DRUG MECHANISM; DRUG SAFETY; DRUG STRUCTURE; DRUG SYNTHESIS; DYSLIPIDEMIA; FANCONI RENOTUBULAR SYNDROME; HEPATITIS B; HERPES VIRUS INFECTION; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; INFECTION PREVENTION; KIDNEY TUBULE DISORDER; LACTIC ACIDOSIS; LIPODYSTROPHY; NEPHROTOXICITY; NONHUMAN; PANCREATITIS; POLYOMA VIRUS; POXVIRUS INFECTION; PRIORITY JOURNAL; RETINITIS; RETROVIRUS INFECTION; REVIEW; VERRUCA VULGARIS; VIRUS INFECTION; ANIMAL; CHEMICAL STRUCTURE; CHEMISTRY; DRUG DESIGN; VIROLOGY;

ANIMALS; ANTIVIRAL AGENTS; DNA VIRUS INFECTIONS; DRUG DESIGN; HUMANS; MOLECULAR STRUCTURE; NUCLEOSIDES; PHOSPHONIC ACIDS;

EID: 27844455955     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd1877     Document Type: Review

References (154)

1. De Clercq, E. et al. A novel selective broad-spectrum anti-DNA virus agent. Nature 323, 464-467 (1986).
2. De Clercq, E. et al. Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines. Antiviral Res. 8, 261-272 (1987).
3. Snoeck, R., Sakuma, T., De Clercq, E., Rosenberg, I. & Holý, A. (S)-1-(3-Hydroxy-2-phosphonylmethoxypropyl)cyt osine, a potent and selective inhibitor of human cytomegalovirus replication. Antimicrob. Agents Chemother. 32, 1839-1844 (1988).
4. Balzarini, J. et al. Marked in vivo antiretrovirus activity of 9-(2-phosphonylmethoxyethyl)adenine, a selective anti-human immunodeficiency virus agent. Proc. Natl Acad. Sci. USA 86, 332-336 (1989).
5. Pauwels, R. et al. Phosphonylmethoxyethyl purine derivatives, a new class of anti-human immunodeficiency virus agents. Antimicrob. Agents Chemother. 32, 1025-1030 (1988).
6. De Clercq, E., Holý, A. & Rosenberg, I. Efficacy of phosphonylmethoxyalkyl derivatives of adenine in experimental herpes simplex virus and vaccinia virus infections in vivo. Antimicrob. Agents Chemother. 33, 185-191 (1989).
7. Balzarini, J. et al. 9-(2-Phosphonylmethoxyethyl)adenine (PMEA) effectively inhibits retrovirus replication in vitro and simian immunodeficiency virus infection in rhesus monkeys. AIDS 5, 21-28 (1991).
8. Holý, A. & Ivanova, G. S. Aliphatic analogues of nucleotides: synthesis and affinity towards nucleases. Nucleic Acids Res. 1, 19-34 (1974).
9. 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 200, 563-565 (1978).
10. Elion, G. B. et al. Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl)guanine. Proc. Natl Acad. Sci. USA 74, 5716-5720 (1977).
11. Schaeffer, H. J. et al. 9-(2-Hydroxyethoxymethyl)guanine activity against viruses of the herpes group. Nature 272, 583-585 (1978).
12. Votruba, I. & Holý, A. Inhibition of S-adenosyl-L-homocysteine hydrolase by the aliphatic nucleoside analogue 9-(S)-(2,3-dihydroxypropyl)adenine. Collect. Czech. Chem. Commun. 45, 3039-3044 (1980).
13. Votruba, I., Holý, A. & De Clercq, E. Metabolism of the broad-spectrum antiviral agent, 9-(S)-(2,3-dihydroxypropyl)adenine, in different cell lines. Acta Virol. 27, 273-276 (1983).
14. Holý, A. Aliphatic analogues of nucleosides, nucleotides and oligonucleotides. Collect. Czech. Chem. Commun. 40, 187-214 (1975).
15. Wolff, M. E. & Burger, A. Analogs of nucleotides. III. Synthesis in the series of adenosine phosphonate derivatives. J. Am. Pharm. Assoc. Am. Pharm. Assoc. (Balti.) 48, 56-59 (1959).
16. Inglot, A. D., Kochman, M. & Mastalerz, P. Antiviral activity of p-nitrobenzylphosphonic acid. Nature 207, 784-785 (1965).
17. Holý, A. Synthesis of 5′-deoxyuridine 5′-phosphonic acid. Tetrahedron Lett. 10, 881-884 (1967).
18. Shipkowitz, N. L. et al. Suppression of herpes simplex virus infection by phosphonoacetic acid. Appl. Microbiol. 26, 264-267 (1973).
19. Holý, A. Phosphonomethoxyalkyl analogs of nucleotides. Curr. Pharm. Des. 9, 2567-2592 (2003).
20. Holý, A. & Rosenberg, I. Synthesis of 9-(2-phosphonylmet hoxyethyl)adenine and related compounds. Collect. Czech. Chem. Commun. 52, 2801-2809 (1987).
21. Holý, A, Rosenberg, I. & Dvoráková, H. Synthesis of N-(2-phosphonylmethoxyethyl) derivatives of heterocyclic bases. Collect. Czech. Chem. Commun. 54, 2190-2210 (1989).
22. Holý, A., Rosenberg, I. & Dvoráková, H. Synthesis of (3-hydroxy-2-phosphonylmethoxypropyl) derivatives of heterocyclic bases. Collect. Czech. Chem. Commun. 54, 2470-2501 (1989).
23. Holý, A. Syntheses of enantiomeric N-(3-hydroxy-2-phosphonomethoxypropyl) derivatives of purine and pyrimidine bases. Collect. Czech. Chem. Commun. 58, 649-674 (1993).
24. Holý, A. & Masojídková, M. Synthesis of enantiomeric N-(2-phosphonomethoxypropyl) derivatives of purine and pyrimidine bases. 1. The stepwise approach. Collect. Czech. Chem. Commun. 60, 1196-1212 (1995).
25. Meerbach, A., Holý, A., Wutzler, P., De Clercq, E. & Neyts, J. Inhibitory effects of novel nucleoside and nucleotide analogues on Epstein-Barr virus replication. Antiviral Chem. Chemother. 9, 275-282 (1998).
26. Holý, A., Votruba, I., Tloustová, E. & Masojídková, M. Synthesis and cytostatic activity of N-[2-(phosphonomethoxy)alkyl] derivatives of N6-substituted adenines, 2,6-diaminopurines and related compounds. Collect. Czech. Chem. Commun. 66, 1545-1592 (2001).
27. Holý, A. Synthetic approaches to 'opened-ring' acyclic nucleoside phosphonates - novel type of antivirals. Collection Symposium Series 5, 24-35 (2002).
28. Votruba, I. et al. Intracellular phosphorylation of broad-spectrum anti-DNA virus agent (S)-9-(3-hydroxy-2-phosph onylmethoxypropyl)adenine and inhibition of viral DNA synthesis. Mol. Pharmacol. 32, 524-529 (1987).
29. Krejcová, R., Horská, K., Votruba, I. & Holý, A. Phosphorylation of purine (phosphonomethoxy)alkyl derivatives by mitochondrial AMP kinase (AK2 type) from L1210 cells. Collect. Czech. Chem. Commun. 65, 1653-1668 (2000).
30. Krejcová, R., Horská, K., Votruba, I. & Holý, A. Interaction of guanine phosphonomethoxyalkyl derivatives with GMP kinase isoenzymes. Biochem. Pharmacol. 60, 1907-1913 (2000).
31. Kramata, P., Votruba, I., Otova, B. & Holý, A. Different inhibitory potencies of acyclic phosphonomethoxyalkyl nucleotide analogs toward DNA polymerases alpha, delta and epsilon. Mol. Pharmacol. 49, 1005-1011 (1996).
32. Naesens, L. et al. HPMPC (cidofovir), PMEA (adefovir) and related acyclic nucleoside phosphonate analogues: A review of their pharmacology and clinical potential in the treatment of viral infections. Antiviral Chem. Chemother. 8, 1-23 (1997).
33. Cihlar, T. & Chen, M. S. Identification of enzymes catalyzing two-step phosphorylation of cidofovir and the effect of cytomegalovirus infection on their activities in host cells. Mol. Pharmacol. 50, 1502-1510 (1996).
34. Merta, A. et al. Phosphorylation of 9-(2-phosphonomethox yethyl)adenine and 9-(S)-(3-hydroxy-2-phosphonomethox ypropyl)adenine by AMP(dAMP) kinase from L1210 cells. Biochem. Pharmacol. 44, 2067-2077 (1992).
35. Neyts, J., Snoeck, R., Balzarini, J. & De Clercq, E. Particular characteristics of the anti-human cytomegalovirus activity of S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)-cytosine (HPMPC) in vitro. Antiviral Res. 16, 41-52 (1991).
36. Ho, H. T. et al. Intracellular metabolism of the antiherpes agent (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cyto sine. Mol. Pharmacol. 41, 197-202 (1992).
37. Birkus, G. et al. Tenofovir diphosphate is a poor substrate and a weak inhibitor of rat DNA polymerases alpha, delta, and epsilon. Antimicrob. Agents Chemother. 46, 1610-1613 (2002).
38. Xiong, X., Smith, J. L. & Chen, M. S. Effect of incorporation of cidofovir into DNA by human cytomegalovirus DNA polymerase on DNA elongation. Antimicrob. Agents Chemother. 41, 594-599 (1997).
39. Tuske, S. et al. Structures of HIV-1 RT-DNA complexes before and after incorporation of the anti-AIDS drug tenofovir. Nature Struct. Mol. Biol. 11, 469-474 (2004).
40. De Clercq, E. Potential of acyclic nucleoside phosphonates in the treatment of DNA virus and retrovirus infections. Expert Rev. Anti-infect. Ther. 1, 21-43 (2003).
41. De Clercq, E. Cidofovir in the treatment of poxvirus infections. Antiviral Res. 55, 1-13 (2002).
42. Helliot, B. et al. The acyclic nucleoside phosphonate analogues, adefovir, tenofovir and PMEDAP, efficiently eliminate banana streak virus from banana (Muss spp.). Antiviral Res. 59, 121-126 (2003).
43. Shen, Y. et al. Selective inhibition of anthrax edema factor by adefovir, a drug for chronic hepatitis B virus infection. Proc. Natl Acad. Sci. USA 101, 3242-3247 (2004).
44. Balzarini, J. et al. The human immunodefciency virus (HIV) inhibitor 9-(2-phosphonylmethoxyethyl)adenine (PMEA) is a strong induce of differentiation of several tumor cell lines. Int. J. Cancer 61, 130-137 (1995).
45. Hatse, S., Naesens, L., De Clercq, E. & Balzarini, J. Potent differentiation-inducing properties of the antiretroviral agent 9-(2-phosphonylmethoxyethyl)adenine (PMEA) in the rat choriocarcinoma (RCHO) tumor cell model. Biochem. Pharmacol. 56, 851-859 (1998).
46. Hatse, S. et al. Potent antitumor activity of the acyclic nucleoside phosphonate 9-(2-phosphonylmethoxyethyl)ad enine in choriocarcinoma-bearing rats. Int. J. Cancer 76, 595-600 (1998).
47. Neyts, J., Sadler, R., De Clercq, E., Raab-Traub, N. & Pagano, J. S. The antiviral agent cidofovir [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine] has pronounced activity against nasopharyngeal carcinoma grown in nude mice. Cancer Res. 58, 384-388 (1998).
48. Murono, S., Raab-Traub, N. & Pagano, J. S. Prevention and inhibition of nasopharyngeal carcinoma growth by antiviral phosphonated nucleoside analogs. Cancer Res. 61, 7875-7877 (2001).
49. Andrei, G., Snoeck, R., Piette, J., Delvenne, P. & De Clercq, E. Inhibiting effects of cidofovir (HPMPC) on the growth of the human cervical carcinoma (SiHa) xenografts in athymic nude mice. Oncol. Res. 10, 533-539 (1998).
50. Liekens, S., Andrei, G., Vandeputte, M., De Clercq, E. & Neyts, J. Potent inhibition of hemangioma formation in rats by the acyclic nucleoside phosphonate analogue cidofovir. Cancer Res. 58, 2562-2567 (1998).
51. Liekens, S., Verbeken, E., De Clercq, E. & Neyts, J. Potent inhibition of hemangiosarcoma development in mice by cidofovir. Int. J. Cancer 92, 161-167 (2001).
52. Liekens, S. et al. Inhibition of fibroblast growth factor-2-induced vascular tumor formation by the acyclic nucleoside phosphonate cidofovir. Cancer Res. 61, 5057-5064 (2001).
53. Andrei, G., Snoeck, R., Schols, D. & De Clercq, E. Induction of apoptosis by cidofovir in human papillomavirus (HPV)-positive cells. Oncol. Res. 12, 397-408 (2001).
54. Abdulkarim, B. et al. Antiviral agent cidofovir restores p53 function and enhances the radiosensitivity in HPV-associated cancers. Oncogene 21, 2334-2346 (2002).
55. Lalezari, J. P. et al. Intravenous cidofovir for peripheral cytomegalovirus retinitis in patients with AIDS. A randomized, controlled trial. Ann. Intern. Med. 126, 257-263 (1997).
56. Hadziyannis, S. J. et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N. Engl. J. Med. 348, 800-807 (2003).
57. Staszewski, S. et al. Efficacy and safety of tenofovir disoproxil fumarate (TDF) versus stavudine (d4T) when used in combination with lamivudine (3TC) and efavirenz (EFV) in HIV-1 infected patients naïve to antiretroviral therapy (ART): 48-week interim results. XIV Intl AIDS Conf. Barcelona, Spain, 7-12 July (2002).
58. De Clercq, E. Clinical potential of the acyclic nucleoside phosphonates cidofovir, adefovir, and tenofovir in treatment of DNA virus and retrovirus infections. Clin. Microbiol. Rev. 16, 569-596 (2003).
59. Robinson, L. G. et al. Progressive multifocal leukoencephalopathy successfully treated with highly active antiretroviral therapy and cidofovir in an adolescent infected with perinatal human immunodeficiency virus (HIV). J. Child Neurol. 19, 35-38 (2004).
60. Milczuk, H. A. Intralesional cidofovir for the treatment of severe juvenile recurrent respiratory papillomatosis: Long-term results in 4 children. Otolaryngol. Head Neck Surg. 128, 788-794 (2003).
61. Chhetri, D. K. & Shapiro, N. L. A scheduled protocol for the treatment of juvenile recurrent respiratory papillomatosis with intralesional cidofovir. Arch. Otolaryngol. Head Neck Surg. 129, 1081-1085 (2003).
62. Mandell, D. L., Arjmand, E. M., Kay, D. J., Casselbrant, M. L. & Rosen, C. A. Intralesional cidofovir for pediatric recurrent respiratory papillomatosis. Arch. Otolaryngol. Head Neck Surg. 130, 1319-1323 (2004).
63. Silverman, D. A. & Pitman, M. J. Current diagnostic and management trends for recurrent respiratory papillomatosis. Curr. Opin. Otolaryngol. Head Neck Surg. 12, 532-537 (2004).
64. de Bilderling, G. et al. Successful use of intralesional and intravenous cidofovir in association with indole-3-carbinol in an 8-year-old girl with pulmonary papillomatosis. J. Med. Virol. 75, 332-335 (2005).
65. Coremans, G. et al. Topical cidofovir (HPMPC) is an effective adjuvant to surgical treatment of anogenital condylomata acuminata. Dis. Colon Rectum 46, 1103-1108 (2003).
66. Calisto, D. & Arcangeli, F. Topical cidofovir for condylomata acuminata of the genitalia in a 3-year-old child. J. Am. Acad. Dermatol. 49, 1192-1193 (2003).
67. DeRossi, S. S. & Laudenbach, J. The management of oral human papillomavirus with topical cidofovir: A case report. Cutis 73, 191-193 (2004).
68. Hatakeyama, N. et al. Successful cidofovir treatment of adenovirus-associated hemorrhagic cystitis and renal dysfunction after allogenic bone marrow transplant. Pediatr. Infect. Dis. J. 22, 928-929 (2003).
69. Fanourgiakis, P. et al. Intravesical instillation of cidofovir in the treatment of hemorrhagic cystitis caused by adenovirus type 11 in a bone marrow transplant recipient. Clin. Infect. Dis. 40, 199-201 (2005).
70. Baxter, K. F. & Highet, A. S. Topical cidofovir and cryotherapy - combination treatment for recalcitrant molluscum contagiosum in a patient with HIV infection. J. Eur. Acad. Dermatol. Venereol. 18, 230-231 (2004).
71. McCabe, D., Weston, B. & Storch, G. Treatment of orf poxvirus lesion with cidofovir seam. Pediatr. Infect. Dis. J. 22, 1027-1028 (2003).
72. Kedes, D. H. & Ganem, D. Sensitivity of Kaposi's sarcoma-associated herpesvirus replication to antiviral drugs. Implications for potential therapy. J. Clin. Invest. 99, 2082-2086 (1977).
73. Neyts, J. & De Clercq, E. Antiviral drug susceptibility of human herpes virus type 8. Antimicrob. Agents Chemother. 41, 2754-2756 (1997).
74. Mazzi, R. et al. Efficacy of cidofovir on human herpesvirus 8 viraemia and Kaposi's sarcoma progression in two patients with AIDS. AIDS 15, 2061-2063 (1997).
75. Fife, K. et al. Cidofovir for the treatment of Kaposi's sarcoma in an HIV-negative homosexual man. Br. J. Dermatol. 141, 1148-1150 (1999).
76. Simonart, T. et al. Treatment of classical Kaposi's sarcoma with intralesional injections of cidofovir: Report of a case. J. Med. Virol. 55, 215-218 (1998).
77. Little, R. F. et al. A pilot study of cidofovir in patients with Kaposi's sarcoma. J. Infect. Dis. 187, 149-153 (2003).
78. Lu, M. et al. Dissection of the Kaposi's sarcoma-associated herpesvirus gene expression program by using the viral DNA replication inhibitor cidofovir. J. Virol. 78, 13637-13652 (2004).
79. Marcellin, P. et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N. Engl. J. Med. 348, 808-816 (2003).
80. Westland, C. et al. Hepatitis B virus genotypes and virologic response in 694 patients in Phase III studies of adefovir dipivoxil. Gastroenterology 125, 107-116 (2003).
81. Perrillo, R. et al. Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus. Gastroenterology 126, 81-90 (2004).
82. Peters, M. G. et al. Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology 126, 91-101 (2004).
83. Jacob, J. R. et al. Suppression of lamivudine-resistant B-domain mutants by adefovir dipivoxil in the woodchuck hepatitis virus model. Antiviral Res. 63, 115-121 (2004).
84. Schiff, E. R. et al. Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients. Hepatology 38, 1419-1427 (2003).
85. Werle-Lapostolle, B. et al. Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy. Gastroenterology 126, 1750-1758 (2004).
86. Squires, K. et al. Tenofovir disoproxil fumarate in nucleoside-resistant HIV-1 infection. Ann. Intern. Med. 139, 313-329 (2003).
87. Gallant, J. E. et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naïve patients. A 3-year randomized trial. J. Am. Med. Assoc. 292, 191-201 (2004).
88. Domingo, P. et al. Improvement of dyslipidemia in patients switching from stavudine to tenofovir: Preliminary results. AIDS 18, 1475-1478 (2004).
89. Gilead announces preliminary 48-week data from study 934 comparing Viread and Emtriva to Combivir both in combination with Sustiva in patients with HIV [online], (2005).
90. Gallant, J. E. & Deresinski, S. Tenofovir disoproxil fumarate. Clin. Infect. Dis. 37, 944-950 (2003).
91. Tsai, C. C. et al. Prevention of SIV infection in macaques by (R)-9-(2-phosphonylmethoxypropyl)adenine. Science 270, 1197-1199 (1995).
92. Dore, G. J. et al. Efficacy of tenofovir disoproxil fumarate in antiretroviral therapy-naïve and -experienced patients coinfected with HIV-1 and hepatitis B virus. J. Infect. Dis. 189, 1185-1192 (2004).
93. Bani-Sadr, F., Palmer, P., Scieux, C. & Molina, J. M. Ninety-six-week efficacy of combination therapy with lamivudine and tenofovir in patients coinfected with HIV-1 and wild-type hepatitis B virus. Clin. Infect. Dis. 39, 1062-1064 (2004).
94. Schildgen, O. et al. Successful therapy of hepatitis B with tenofovir in HIV-infected patients failing previous adefovir and lamivudine treatment. AIDS 18, 2325-2327 (2004).
95. van Bömmel, F. et al. Comparison of adefovir and tenofovir in the treatment of lamivudine-resistant hepatitis B virus infection. Hepatology 40, 1421-1425 (2004).
96. Cundy, K. C., Shaw, J. P. & Lee, W. A. Oral, subcutaneous, and intramuscular bioavailabilities of the antiviral nucleotide analog 9-(2-phosphonylmethoxyethyl) adenine in cynomolgus monkeys. Antimicrob. Agents Chemother. 38, 365-368 (1994).
97. Cundy, K. C., Hitchcock, M. J. & Lee, W. A. Pharmacokinetics of cidofovir in monkeys. Evidence for a prolonged elimination phase representing phosphorylated drug. Drug Metab. Dispos. 24, 738-744 (1996).
98. Cundy, K. C. Clinical pharmacokinetics of the antiviral nucleotide analogues cidofovir and adefovir. Clin. Pharmacokinet. 36, 127-143 (1999).
99. Shaw, J. P. et al. Metabolism and pharmacokinetics of novel oral prodrugs of 9-[(R)-2-(phosphonomethoxy)propyl ]adenine (PMPA) in dogs. Pharm. Res. 14, 1824-1829 (1997).
100. Starrett, J. E. Jr., Tortolani, D. R., Hitchcock, M. J., Martin, J. C. & Mansuri, M. M. Synthesis and in vitro evaluation of a phosphonate prodrug: Bis(pivaloyloxymethyl) 9-(2-phosp honylmethoxyethyl)adenine. Antiviral Res. 19, 267-273 (1992).
101. Cundy, K. C. et al. Oral bioavailability of the antiretroviral agent 9-(2-phosphonylmethoxyethyl)adenine (PMEA) from three formulations of the prodrug bis(pivaloyloxymethyl)-PMEA in fasted male cynomolgus monkeys. Pharm. Res. 11, 839-843 (1994).
102. Cundy, K. C. et al. Oral formulations of adefovir dipivoxil: In vitro dissolution and in vivo bioavailability in dogs. J. Pharm. Sci. 86, 1334-1338 (1997).
103. Shaw, J. P. et al. Pharmacokinetics and metabolism of selected prodrugs of PMEA in rats. Drug Metab. Dispos. 25, 362-366 (1997).
104. Neyts, J., Leyssen, P., Verbeken, E. & De Clercq, E. Efficacy of cidofovir in a murine model of disseminated progressive vaccinia. Antimicrob. Agents Chemother. 48, 2267-2273 (2004).
105. Quenelle, D. C., Collins, D. J. & Kern, E. R. Cutaneous infections of mice with vaccinia or cowpox viruses and efficacy of cidofovir. Antiviral Res. 63, 33-40 (2004).
106. Roy, C. J., Baker, R., Washburn, K. & Bray, M. Aerosolized cidofovir is retained in the respiratory tract and protects mice against intranasal cowpox virus challenge. Antimicrob. Agents Chemother. 47, 2933-2937 (2003).
107. Kaneko, H. et al. The cotton rat model for adenovirus ocular infection: antiviral activity of cidofovir. Antiviral Res. 61, 63-66 (2004).
108. Bischofberger, N. et al. 1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosine, an intracellular prodrug for (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl) cytosine with improved therapeutic index in vivo. Antimicrob. Agents Chemother. 38, 2387-2391 (1994).
109. Cundy, K. C. et al. Clinical pharmacokinetics of 1-[((S-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosine in human immunodeficiency virus-infected patients. Antimicrob. Agents Chemother. 43, 271-277 (1999).
110. Oliyai, R. et al. Aryl ester prodrugs of cyclic HPMPC. I: Physicochemical characterization and in vitro biological stability. Pharm. Res. 16, 1687-1693 (1999).
111. 14C]cidofovir in MRC-5 human lung fibroblasts is explained by unique cellular uptake and metabolism. Mol. Pharmacol. 63, 678-681 (2003).
112. Kern, E. R. et al. Enhanced inhibition of orthopoxvirus replication in vitro by alkoxyalkyl esters of cidofovir and cyclic cidofovir. Antimicrob. Agents Chemother. 46, 991-995 (2002).
113. Beadle, J. R. et al. Alkoxyalkyl esters of cidofovir and cyclic cidofovir exhibit multiple-log enhancement of antiviral activity against cytomegalovirus and herpesvirus replication in vitro. Antimicrob. Agents Chemother. 46, 2381-2386 (2002).
114. Hartline, C. B. et al. Ether lipid-ester prodrugs of acyclic nucleoside phosphonates: Activity against adenovirus replication in vitro. J. Infect. Dis. 191, 396-399 (2005).
115. Buller, R. M. et al. Efficacy of oral active ether lipid analogs of cidofovir in a lethal mousepox model. Virology 318, 474-481 (2004).
116. Kern, E. R. et al. Oral treatment of murine cytomegalovirus infections with ether lipid esters of cidofovir. Antimicrob. Agents Chemother. 48, 3516-3522 (2004).
117. Bidanset, D. J., Beadle, J. R., Wan, W. B., Hostetler, K. Y. & Kern, E. R. Oral activity of ether lipid ester prodrugs of cidofovir against experimental human cytomegalovirus infection. J. Infect. Dis. 190, 499-503 (2004).
118. Cihlar, T., Fuller, M. D., Mulato, A. S. & Cherrington, J. M. A point mutation in the human cytomegalovirus DNA polymerase gene selected in vitro by cidofovir confers a slow replication phenotype in cell culture. Virology 248, 382-393 (1998).
119. Chou, S., Lurain, N. S., Thompson, K. D., Miner, R. C. & Drew, W. L. Viral DNA polymerase mutations associated with drug resistance in human cytomegalovirus. J. Infect. Dis. 188, 32-39 (2003).
120. Andrei, G. et al. Resistance of herpes simplex virus type 1 against different phosphonylmethoxyalkyl derivatives of purines and pyrimidines due to specific mutations in the viral DNA polymerase gene. J. Gen. Virol, 81, 639-648 (2000).
121. Smee, D. F., Sidwell, R. W., Kefauver, D., Bray, M. & Huggins, J. W. Characterization of wild-type and cidofovir-resistant strains of camelpox, cowpox, monkeypox, and vaccinia viruses. Antimicrob. Agents Chemother. 46, 1329-1335 (2002).
122. Andrei, G., Fiten, P., De Clercq, E., Opdenakker, G. & Snoeck, R. Reduced pathogenicity of phenotypically and genotypically characterized cidofovir (CDV)-resistant vaccinia virus (VV). 18th Intl Conf. Antiviral Res. Barcelona, Spain, 10-14 April (Abstract no. A82) (2005).
123. Yang, H. et al. Resistance surveillance in chronic hepatitis B patients treated with adefovir dipivoxil for up to 60 weeks. Hepatology 36, 464-473 (2002).
124. Westland, C. E. et al. Week 48 resistance surveillance in two phase 3 clinical studies of adefovir dipivoxil for chronic hepatitis B. Hepatology 38, 96-103 (2003).
125. Angus, P. et al. Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase. Gastroenterology 125, 292-297 (2003).
126. Delaney, W. E. IV et al. The hepatitis B virus polymerase mutation rtV173L is selected during lamivudine therapy and enhances viral replication in vitro. J. Virol. 77, 11833-11841 (2003).
127. Lada, O. et al. In vitro susceptibility of lamivudine-resistant hepatitis B virus to adefovir and tenofovir. Antiviral Ther. 9, 353-363 (2004).
128. Margot, N. A. et al. Genotypic and phenotypic analyses of HIV-1 in antiretroviral-experienced patients treated with tenofovir DF. AIDS 16, 1227-1235 (2002).
129. Murry, J. P. et al. Reversion of the M184V mutation in simian immunodeficiency virus reverse transcriptase is selected by tenofovir, even in the presence of lamivudine. J. Virol. 77, 1120-1130 (2003).
130. Wolf, K. et al. Tenofovir resistance and resensitization. Antimicrob. Agents Chemother. 47, 3478-3484 (2003).
131. Deval, J. et al. Mechanistic basis for reduced viral and enzymatic fitness of HIV-1 reverse transcriptase containing both K65R and M184V mutations. J. Biol. Chem. 279, 509-516 (2004).
132. Miller, M. D. et al. Genotypic and phenotypic predictors of the magnitude of response to tenofovir disoproxil fumerate treatment in antiretroviral-experienced patients. J. Infect. Dis. 189, 837-846 (2004).
133. Cundy, K. C., Li, Z. H. & Lee, W. A. Effect of probenecid on the distribution, metabolism, and excretion of cidofovir in rabbits. Drug Metab. Dispos. 24, 315-321 (1996).
134. Lacy, S. A., Hitchcock, M. J., Lee, W. A., Tellier, P. & Cundy, K. C. Effect of oral probenecid coadministration on the chronic toxicity and pharmacokinetics of intravenous cidofovir in cynomolgus monkeys. Toxicol. Sci. 44, 97-106 (1998).
135. Cundy, K. C. et al. Pharmacokinetics, bioavailability, metabolism, and tissue distribution of cidofovir (HPMPC) and cyclic HPMPC in rats. Drug Metab. Dispos. 24, 745-752 (1996).
136. Peyrière, H. et al. Renal tubular dysfunction associated with tenofovir therapy. Report of 7 cases. J. Acquir. Immune Defic. Syndr. 35, 269-273 (2004).
137. Barrios, A., Garciá-Benayas, T., González-Lahoz, J. & Soriano, V. Tenofovir-related nephrotoxicity in HIV-infected patients. AIDS 18, 960-962 (2004).
138. Gaspar, G., Monereo, A., García-Reyne, A. & de Guzmán, M. Fanconi syndrome and acute renal failure in a patient treated with tenofovir: A call for caution. AIDS 18, 351-352 (2004).
139. Karras, A. et al. Tenofovir-related nephrotoxicity in human immunodeficiency virus-infected patients: Three cases of renal failure, Fanconi syndrome, and nephrogenic diabetes insipidus. Clin. Infect. Dis. 36, 1070-1073 (2003).
140. Rifkin, B. S. & Perazella, M. A. Tenofovir-associated nephrotoxicity: Fanconi syndrome and renal failure. Am. J. Med. 117, 282-284 (2004).
141. Izzedine, H. et al. Renal safety of tenofovir in HIV treatment-experienced patients. AIDS 18, 1074-1075 (2004).
142. Rollot, F. et al. Tenofovir-related Fanconi syndrome with nephrogenic diabetes insipidus in a patient with acquired immunodeficiency syndrome: the role of lopinavir-ritonavir-didanosine. Clin. Infect. Dis. 37, e174-e176 (2003).
143. Martinez, E. et al. Pancreatic toxic effects associated with co-administration of didanosine and tenofovir in HIV-infected adults. Lancet 364, 65-67 (2004).
144. Callens, S., De Schacht, C., Huyst, V. & Colebunders, R. Pancreatitis in an HIV-infected person on a tenofovir, didanosine and stavudine containing highly active antiretroviral treatment. J. Infect. 47, 188-189 (2003).
145. Murphy, M. D., O'Hearn, M. & Chou, S. Fatal lactic acidosis and acute renal failure after addition of tenofovir to an antiretroviral regimen containing didanosine. Clin. Infect. Dis. 36, 1082-1085 (2003).
146. Moyle, G. & Boffito, M. Unexpected drug interactions and adverse events with antiretroviral drugs. Lancet 364, 8-10 (2004).
147. Lee, W. A. et al. Selective intracellular activation of a novel prodrug of the human immunodeficiency virus reverse transcriptase inhibitor tenofovir leads to preferential distribution and accumulation in lymphatic tissue. Antimicrob. Agents Chemother. 49, 1898-1906 (2005).
148. Holý, A. et al. 6-[2-(Phosphonomethoxy)alkoxy]pyrimidine s with antiviral activity. J. Med. Chem. 45, 1918-1929 (2002).
149. Balzarini, J. et al. Antiretrovirus activity of a novel class of acyclic pyrimidine nucleoside phosphonates. Antimicrob. Agents Chemother. 46, 2185-2193 (2002).
150. Hocková, D. et al. 5-Substituted-2,4-diamino-6-[2-(phosp honomethoxy)ethoxy]pyrimidines-acyclic nucleoside phosphonate analogues with antiviral activity. J. Med. Chem. 46, 5064-5073 (2003).
151. Balzarini, J. et al. 6-[2-(Phosphonomethoxy)alkoxy]-2,4-diaminopyrimidines: A new class of acyclic pyrimidine nucleoside phosphonates with antiviral activity. Nucleosides Nucleotides Nucleic Acids 23, 1321-1327 (2004).
152. De Clercq, E. et al. Antiviral potential of a new generation of acyclic nucleoside phosphonates, the 6-[2-(phosphono methoxy)alkoxy]-2,4-diaminopyrimidines. Nucleosides Nucleotides Nucleic Acids (in the press).
153. Ying, C. et al. Novel acyclic nucleoside phosphonate analogues with potent anti-hepatitis B virus activities. Antimicrob. Agents Chemother. 49, 1177-1180 (2005).
154. Naesens, L. et al. Antiadenovirus activities of several classes of nucleoside and nucleotide analogues. Antimicrob. Agents Chemother. 49, 1010-1016 (2005).