scholarly journals Clinical Potential of the Acyclic Nucleoside Phosphonates Cidofovir, Adefovir, and Tenofovir in Treatment of DNA Virus and Retrovirus Infections

2003 ◽  
Vol 16 (4) ◽  
pp. 569-596 ◽  
Author(s):  
Erik De Clercq
Keyword(s):  
Hepatitis B ◽  
Tenofovir Disoproxil Fumarate ◽  
Adefovir Dipivoxil ◽  
Cowpox Virus ◽  
Virus Infections ◽  
Molluscum Contagiosum Virus ◽  
Dna Virus ◽  
Immunodeficiency Virus ◽  
Acyclic Nucleoside Phosphonates ◽  
Acyclic Nucleoside

SUMMARY The acyclic nucleoside phosphonates HPMPC (cidofovir), PMEA (adefovir), and PMPA (tenofovir) have proved to be effective in vitro (cell culture systems) and in vivo (animal models and clinical studies) against a wide variety of DNA virus and retrovirus infections: cidofovir against herpesvirus (herpes simplex virus types 1 and 2 varicella-zoster virus, cytomegalovirus [CMV], Epstein-Barr virus, and human herpesviruses 6, 7, and 8), polyomavirus, papillomavirus, adenovirus, and poxvirus (variola virus, cowpox virus, vaccinia virus, molluscum contagiosum virus, and orf virus) infections; adefovir against herpesvirus, hepadnavirus (human hepatitis B virus), and retrovirus (human immunodeficiency virus types 1 [HIV-1] and 2 [HIV-2], simian immunodeficiency virus, and feline immunodeficiency virus) infections; and tenofovir against both hepadnavirus and retrovirus infections. Cidofovir (Vistide) has been officially approved for the treatment of CMV retinitis in AIDS patients, tenofovir disoproxil fumarate (Viread) has been approved for the treatment of HIV infections (i.e., AIDS), and adefovir dipivoxil (Hepsera) has been approved for the treatment of chronic hepatitis B. Nephrotoxicity is the dose-limiting side effect for cidofovir (Vistide) when used intravenously (5 mg/kg); no toxic side effects have been described for adefovir dipivoxil and tenofovir disoproxil fumarate, at the approved doses (Hepsera at 10 mg orally daily and Viread at 300 mg orally daily).

scholarly journals Evaluation of Nucleoside Phosphonates and Their Analogs and Prodrugs for Inhibition of Orthopoxvirus Replication

2003 ◽  
Vol 47 (7) ◽  
pp. 2193-2198 ◽  
Author(s):  
Kathy A. Keith ◽  
Michael J. M. Hitchcock ◽  
William A. Lee ◽  
Antonin Holý ◽  
Earl R. Kern
Keyword(s):  
Vaccinia Virus ◽  
Cowpox Virus ◽  
Active Compounds ◽  
Culture Cells ◽  
Tissue Culture Cells ◽  
B Virus ◽  
Immunodeficiency Virus ◽  
Acyclic Nucleoside Phosphonates ◽  
Acyclic Nucleoside

ABSTRACT In the event of a bioterrorism attack using smallpox virus, there currently is no approved drug for the treatment of infections with this virus. We have reported previously that (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (HPMPC) (also known as cidofovir [CDV]) has good activity against poxvirus infections; however, a major limitation is the requirement for intravenous administration. Two related acyclic nucleoside phosphonates (ANPs), adefovir (PMEA) and tenofovir (PMPA), are active against human immunodeficiency virus or hepatitis B virus but do not have activity against the orthopoxviruses. Therefore, we have evaluated a number of analogs and potential oral prodrugs of these three compounds for their ability to inhibit the replication of vaccinia virus or cowpox virus in tissue culture cells. The most-active compounds within the CDV series were (S)-HPMPA and (butyl l-alaninyl) cyclic HPMPC, with 50% effective concentrations (EC50s) from 4 to 8 μM, compared with 33 to 43 μM for CDV. Although PMEA itself was not active, adefovir dipivoxil {bis[(pivaloyl)oxymethyl] PMEA} and bis(butyl l-alaninyl) PMEA were active against both viruses, and bis(butyl l-alaninyl) PME-N6-(cyclopropyl)DAP and (isopropyl l-alaninyl)phenyl PME-N6-(cyclopropyl)DAP were the most active compounds tested, with EC50s of 0.1 to 2.6 μM. In the PMPA series, none of the analogs tested had significantly better activity than PMPA itself. These data indicate that a number of these ANP derivatives have activity against vaccinia virus and cowpox virus in vitro and should be evaluated for their efficacies in animal models.

scholarly journals Activities of Different Classes of Acyclic Nucleoside Phosphonates against BK Virus in Primary Human Renal Cells

2011 ◽  
Vol 55 (5) ◽  
pp. 1961-1967 ◽  
Author(s):  
D. Topalis ◽  
I. Lebeau ◽  
M. Krečmerová ◽  
G. Andrei ◽  
R. Snoeck
Keyword(s):  
Graft Loss ◽  
Bk Virus ◽  
Virus Infections ◽  
Renal Cells ◽  
Dna Virus ◽  
Transplant Patients ◽  
Proximal Tubular Epithelial Cells ◽  
Acyclic Nucleoside Phosphonates ◽  
Acyclic Nucleoside ◽  
Renal Proximal Tubular

ABSTRACTBK virus (BKV), a virus belonging to the polyomavirus family, is a circular double-stranded DNA virus that causes nephropathies in immunocompromised patients after kidney or bone marrow transplantation. The occurrence of polyomavirus-associated nephropathy in kidney transplant patients may trigger graft loss, and guidelines for the management of BKV infection have not yet been clearly established. Treatment of BKV nephropathy with cidofovir (CDV) {(S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (HPMPC)}, an acyclic phosphonate analogue of dCMP with a broad antiviral activity against DNA virus infections, has been proposed. The benefit of this small-molecule-based treatment has been evaluated only with a limited number of cases. In this study, we report the evaluation of three different classes of acyclic nucleoside phosphonates for their activities against BKV replication in two different primary renal cells: renal proximal tubular epithelial cells (RPTECs) and human renal cortical epithelial (HRCE) cells. The data indicate that besides HPMPC and its cyclic form, (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine (HPMP-5-azaC), cyclic HPMP (cHPMP)-5-azaC, hexadecyloxyethyl (HDE)-cHPMP-5-azaC, and 9-[2-(phosphonomethoxy)ethyl]guanine (PMEG) are the most selective inhibitors of BKV replication. On the contrary, leflunomide, which has also been proposed for the management of BKV-associated diseases, is not able to inhibit BKV replication at nontoxic concentrations.

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