Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Acyclic nucleoside phosphonates: a key class of antiviral drugs

Key Points

  • Acyclic nucleoside phosphonates (ANPs) bring a new dimension to the therapy of viral infections, as they offer a broader spectrum of activity, a longer duration of antiviral action and a lower risk of resistance development compared with available treatments.

  • The key factor underlying all these unique features is the presence of the phosphonate group, which allows ANPs to interfere with the normal pathway of nucleic acid biosynthesis, and, in particular, viral nucleic acid biosynthesis.

  • Three ANPs (cidofovir, adefovir and tenofovir) have been marketed worldwide. They are active against virtually all key DNA viruses and retroviruses.

  • Cidofovir has proved to be effective in the treatment of herpes-, papilloma-, polyoma-, adeno- and pox-virus infections. It has been formally approved for intravenous use in the treatment of cytomegalovirus retinitis in AIDS patients.

  • Adefovir in its oral prodrug form, adefovir dipivoxil, has been licensed for the treatment of chronic hepatitis B virus infections.

  • Tenofovir has been licensed in its oral prodrug form, tenofovir disoproxil fumarate (TDF), for the treatment of human immunodeficiency virus infections (that is, AIDS), and has also been marketed as a fixed-dose combination with the nucleoside analogue emtricitabine. This combination, provided as a single pill once daily, can be considered as the cornerstone of AIDS therapies. TDF alone and combined with emtriva also has great potential for the treatment of chronic hepatitis B.

  • This article describes the history of ANPs, summarizing their chemistry, mechanisms of action and clinical applications, as well as current developments in the field.

Abstract

Almost 20 years after the broad antiviral activity spectrum of the first acyclic nucleoside phosphonates was described, several of these compounds have become important therapies for DNA virus and retrovirus infections. Here, we review the discovery and development of acyclic nucleoside phosphonates, focusing on cidofovir and its potential in the treatment of various herpes-, papilloma-, polyoma-, adeno- and pox-virus infections, adefovir for the treatment of hepatitis B and tenofovir for the treatment of AIDS and the prevention of HIV infections.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Acyclic nucleoside phosphonates.
Figure 2: Mechanism of action of cidofovir and adefovir.
Figure 3: Key clinical data for acyclic nucleoside phosphonates.
Figure 4: New generation of acyclic nucleoside phosphonates.
Figure 5: Optimized computed conformations of a new acyclic nucleoside phosphonate.

Similar content being viewed by others

References

  1. De Clercq, E. et al. A novel selective broad-spectrum anti-DNA virus agent. Nature 323, 464–467 (1986). First description of a unique class of antiviral agents represented by ( S )-9-(3-hydroxyl-2-phosphonylmethoxypropyl)adenine and PMEA (adefovir), which would later be used (as Hepsera) for the treatment of chronic hepatitis B.

    Article  CAS  PubMed  Google Scholar 

  2. De Clercq, E. et al. Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines. Antiviral Res. 8, 261–272 (1987). First description of the antiviral activity of ( S )-1-(3-hydroxyl-2-phosphonyl-methoxypropyl)cytosine, which nine years later would be launched (as Vistide) for the treatment of CMV in AIDS patients.

    Article  CAS  PubMed  Google Scholar 

  3. Snoeck, R., Sakuma, T., De Clercq, E., Rosenberg, I. & Holý, A. (S)-1-(3-Hydroxy-2-phosphonylmethoxypropyl)cytosine, a potent and selective inhibitor of human cytomegalovirus replication. Antimicrob. Agents Chemother. 32, 1839–1844 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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). First description of in vivo antiretroviral activity of PMEA in a murine retrovirus (Moloney sarcoma virus) model, which would subsequently serve as the experimental model for demonstrating in vivo antiretroviral activity of R -PMPA (tenofovir).

    Article  CAS  PubMed  Google Scholar 

  5. Pauwels, R. et al. Phosphonylmethoxyethyl purine derivatives, a new class of anti-human immunodeficiency virus agents. Antimicrob. Agents Chemother. 32, 1025–1030 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  8. Holý, A. & Ivanova, G. S. Aliphatic analogues of nucleotides: synthesis and affinity towards nucleases. Nucleic Acids Res. 1, 19–34 (1974).

    Article  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  11. Schaeffer, H. J. et al. 9-(2-Hydroxyethoxymethyl)guanine activity against viruses of the herpes group. Nature 272, 583–585 (1978). References 10 and 11 describe the antiherpetic activity of acyclovir, which is still considered the 'gold' standard for the treatment of HSV and VZV infections.

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  14. Holý, A. Aliphatic analogues of nucleosides, nucleotides and oligonucleotides. Collect. Czech. Chem. Commun. 40, 187–214 (1975).

    Article  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  16. Inglot, A. D., Kochman, M. & Mastalerz, P. Antiviral activity of p-nitrobenzylphosphonic acid. Nature 207, 784–785 (1965).

    Article  CAS  PubMed  Google Scholar 

  17. Holý, A. Synthesis of 5′-deoxyuridine 5′-phosphonic acid. Tetrahedron Lett. 10, 881–884 (1967).

    Article  PubMed  Google Scholar 

  18. Shipkowitz, N. L. et al. Suppression of herpes simplex virus infection by phosphonoacetic acid. Appl. Microbiol. 26, 264–267 (1973).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Holý, A. Phosphonomethoxyalkyl analogs of nucleotides. Curr. Pharm. Des. 9, 2567–2592 (2003).

    Article  PubMed  Google Scholar 

  20. Holý, A. & Rosenberg, I. Synthesis of 9-(2-phosphonylmethoxyethyl)adenine and related compounds. Collect. Czech. Chem. Commun. 52, 2801–2809 (1987).

    Article  Google Scholar 

  21. Holý, A., Rosenberg, I. & Dvoráková, H. Synthesis of N-(2-phosphonylmethoxyethyl) derivatives of heterocyclic bases. Collect. Czech. Chem. Commun. 54, 2190–2210 (1989).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  Google Scholar 

  27. Holý, A. Synthetic approaches to 'opened-ring' acyclic nucleoside phosphonates — novel type of antivirals. Collection Symposium Series 5, 24–35 (2002).

    Google Scholar 

  28. Votruba, I. et al. Intracellular phosphorylation of broad-spectrum anti-DNA virus agent (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine and inhibition of viral DNA synthesis. Mol. Pharmacol. 32, 524–529 (1987).

    CAS  PubMed  Google Scholar 

  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).

    Article  Google Scholar 

  30. Krejcová, R., Horská, K., Votruba, I. & Holý, A. Interaction of guanine phosphonomethoxyalkyl derivatives with GMP kinase isoenzymes. Biochem. Pharmacol. 60, 1907–1913 (2000).

    Article  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  34. Merta, A. et al. Phosphorylation of 9-(2-phosphonomethoxyethyl)adenine and 9-(S)-(3-hydroxy-2-phosphonomethoxypropyl)adenine by AMP(dAMP) kinase from L1210 cells. Biochem. Pharmacol. 44, 2067–2077 (1992).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  36. Ho, H. T. et al. Intracellular metabolism of the antiherpes agent (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine. Mol. Pharmacol. 41, 197–202 (1992).

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  41. De Clercq, E. Cidofovir in the treatment of poxvirus infections. Antiviral Res. 55, 1–13 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Helliot, B. et al. The acyclic nucleoside phosphonate analogues, adefovir, tenofovir and PMEDAP, efficiently eliminate banana streak virus from banana (Musa spp.). Antiviral Res. 59, 121–126 (2003).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  44. Balzarini, J. et al. The human immunodeficiency virus (HIV) inhibitor 9-(2-phosphonylmethoxyethyl)adenine (PMEA) is a strong inducer of differentiation of several tumor cell lines. Int. J. Cancer 61, 130–137 (1995).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  46. Hatse, S. et al. Potent antitumor activity of the acyclic nucleoside phosphonate 9-(2-phosphonylmethoxyethyl)adenine in choriocarcinoma-bearing rats. Int. J. Cancer 76, 595–600 (1998).

    Article  CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Article  Google Scholar 

  54. Abdulkarim, B. et al. Antiviral agent cidofovir restores p53 function and enhances the radiosensitivity in HPV-associated cancers. Oncogene 21, 2334–2346 (2002).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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). Describes the pioneering clinical studies that justified the use of adefovir dipivoxil for the treatment of HB e Ag-negative HBV infections.

    Article  CAS  PubMed  Google Scholar 

  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). Complements our review by providing more detailed information on the clinical aspects of the ANPs in the treatment of various DNA virus and retrovirus infections.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  67. DeRossi, S. S. & Laudenbach, J. The management of oral human papillomavirus with topical cidofovir: a case report. Cutis 73, 191–193 (2004).

    PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  71. McCabe, D., Weston, B. & Storch, G. Treatment of orf poxvirus lesion with cidofovir cream. Pediatr. Infect. Dis. J. 22, 1027–1028 (2003).

    Article  PubMed  Google Scholar 

  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).

    Article  Google Scholar 

  73. Neyts, J. & De Clercq, E. Antiviral drug susceptibility of human herpes virus type 8. Antimicrob. Agents Chemother. 41, 2754–2756 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  77. Little, R. F. et al. A pilot study of cidofovir in patients with Kaposi's sarcoma. J. Infect. Dis. 187, 149–153 (2003).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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). Describes the pioneering clinical studies that justified the use of adefovir dipivoxil for the treatment of HB e Ag-positive HBV infections.

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  86. Squires, K. et al. Tenofovir disoproxil fumarate in nucleoside-resistant HIV-1 infection. Ann. Intern. Med. 139, 313–320 (2003).

    Article  CAS  PubMed  Google Scholar 

  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). Crucial 3-year clinical study that proved the superiority of TDF over stavudine, both in combination with lamivudine and efavirenz, in HIV-infected individuals not previously exposed to antiretroviral drug treatment.

    Article  CAS  Google Scholar 

  88. Domingo, P. et al. Improvement of dyslipidemia in patients switching from stavudine to tenofovir: preliminary results. AIDS 18, 1475–1478 (2004).

    Article  PubMed  Google Scholar 

  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], <http://www.gilead.com/wt/sec/pr_670153#uphere> (2005).

  90. Gallant, J. E. & Deresinski, S. Tenofovir disoproxil fumarate. Clin. Infect. Dis. 37, 944–950 (2003).

    Article  CAS  PubMed  Google Scholar 

  91. Tsai, C. C. et al. Prevention of SIV infection in macaques by (R)-9-(2-phosphonylmethoxypropyl)adenine. Science 270, 1197–1199 (1995). Pioneering study showing the efficacy of tenofovir in the prevention of SIV infection in macaques. Now, ten years later, this study can be considered as the model for the oral administration of TDF (one pill a day) in the prevention of HIV infections.

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  98. Cundy, K. C. Clinical pharmacokinetics of the antiviral nucleotide analogues cidofovir and adefovir. Clin. Pharmacokinet. 36, 127–143 (1999).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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-phosphonylmethoxyethyl)adenine. Antiviral Res. 19, 267–273 (1992).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  103. Shaw, J. P. et al. Pharmacokinetics and metabolism of selected prodrugs of PMEA in rats. Drug Metab. Dispos. 25, 362–366 (1997).

    CAS  PubMed  Google Scholar 

  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). Describes the protective activity of cidofovir in a unique animal model for disseminated progressive vaccinia, reminiscent of the complications that could be expected from the inadvertent inoculation of immunosuppressed patients with the smallpox vaccine (vaccinia).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Kaneko, H. et al. The cotton rat model for adenovirus ocular infection: antiviral activity of cidofovir. Antiviral Res. 61, 63–66 (2004).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  111. Aldern, K. A., Ciesla, S. L., Winegarden, K. L. & Hostetler, K. Y. Increased antiviral activity of 1-O-hexadecyloxypropyl-[2-14C]cidofovir in MRC-5 human lung fibroblasts is explained by unique cellular uptake and metabolism. Mol. Pharmacol. 63, 678–681 (2003).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Lada, O. et al. In vitro susceptibility of lamivudine-resistant hepatitis B virus to adefovir and tenofovir. Antiviral Ther. 9, 353–363 (2004).

    CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Wolf, K. et al. Tenofovir resistance and resensitization. Antimicrob. Agents Chemother. 47, 3478–3484 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  132. Miller, M. D. et al. Genotypic and phenotypic predictors of the magnitude of response to tenofovir disoproxil fumarate treatment in antiretroviral-experienced patients. J. Infect. Dis. 189, 837–846 (2004).

    Article  CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  137. Barrios, A., Garciá-Benayas, T., González-Lahoz, J. & Soriano, V. Tenofovir-related nephrotoxicity in HIV-infected patients. AIDS 18, 960–962 (2004).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  140. Rifkin, B. S. & Perazella, M. A. Tenofovir-associated nephrotoxicity: Fanconi syndrome and renal failure. Am. J. Med. 117, 282–284 (2004).

    Article  CAS  PubMed  Google Scholar 

  141. Izzedine, H. et al. Renal safety of tenofovir in HIV treatment-experienced patients. AIDS 18, 1074–1075 (2004).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  146. Moyle, G. & Boffito, M. Unexpected drug interactions and adverse events with antiretroviral drugs. Lancet 364, 8–10 (2004).

    Article  PubMed  Google Scholar 

  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). Focuses on an interesting concept — through the design of the appropriate prodrug adducts, tissue distribution of the drug can be modulated and the active drug (in this case tenofovir) can be channelled towards the preferred organ (that is, lymphatic tissue).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Holý, A. et al. 6-[2-(Phosphonomethoxy)alkoxy]pyrimidines with antiviral activity. J. Med. Chem. 45, 1918–1929 (2002). References 148 and 149 report on a novel class of ANPs, the 6-[2-(phosphonomethoxy)alkoxy]pyrimi-dines, which warrant further investigation for their potential in the treatment of those virus infections that have proven amenable to therapy with cidofovir, adefovir or tenofovir.

    Article  CAS  PubMed  Google Scholar 

  149. Balzarini, J. et al. Antiretrovirus activity of a novel class of acyclic pyrimidine nucleoside phosphonates. Antimicrob. Agents Chemother. 46, 2185–2193 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Hocková, D. et al. 5-Substituted-2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]pyrimidines-acyclic nucleoside phosphonate analogues with antiviral activity. J. Med. Chem. 46, 5064–5073 (2003).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  152. De Clercq, E. et al. Antiviral potential of a new generation of acyclic nucleoside phosphonates, the 6-[2-(phosphonomethoxy)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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Naesens, L. et al. Antiadenovirus activities of several classes of nucleoside and nucleotide analogues. Antimicrob. Agents Chemother. 49, 1010–1016 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Special thanks go to C. Callebaut for invaluable editorial assistance. We are extremely grateful to Z. Havlas (Institute of Organic Chemistry and Biochemistry) for his help with the calculation of optimized structures and his contribution to the preparation of the manuscript.

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The authors are both co-inventors of the acyclic nucleoside phosphonates described in the present review.

Related links

Related links

DATABASES

OMIM

Hepatitis C virus

HHV-6

Human immunodeficiency virus

Kaposi's sarcoma

Glossary

NUCLEOSIDE

Purine or pyrimidine base linked to ribose or deoxyribose. Nucleotides, which are formed from nucleosides by the addition of phosphate groups, are the building blocks of DNA and RNA.

NUCLEOSIDE LINKAGE

The link between the purine or pyrimidine base and the ribose or deoxyribose.

PRODRUG

A pharmacologically inactive compound that is converted to the active form of the drug by endogenous enzymes or metabolism. A prodrug is generally designed to overcome problems associated with stability, toxicity, lack of specificity or limited (oral) bioavailability.

ISOPOLARITY

Similar charge, as shown by a phosphonate with regard to a phosphate linkage.

ISOSTERE

Similar spatial (steric) size.

SYNTHON

A structural unit within a molecule that is related to a possible synthetic operation.

CONGENER

Any particular member of the same chemical family.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Clercq, E., Holý, A. Acyclic nucleoside phosphonates: a key class of antiviral drugs. Nat Rev Drug Discov 4, 928–940 (2005). https://doi.org/10.1038/nrd1877

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd1877

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing