Acyclic Nucleoside Phosphonates in the Chemotherapy of DNA Virus and Retrovirus Infections

Clercq, Erik De

doi:10.1159/000150563

Cited by 72 publications

(28 citation statements)

References 17 publications

(22 reference statements)

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“…These drugs have been shown to be effective against a wide range of DNA viruses and retroviruses (reviewed in reference 8), and one of these compounds, (S)-1-[3-hydroxy-2-(phosphonylmethoxypropyl)]cytosine, also known as cidofovir (CDV), has been granted Food and Drug Administration approval for the treatment of cytomegalovirus (CMV)-induced retinitis. CDV has been used off label in the treatment of orf (11) and molluscum contagiosum (21) virus infections.…”

mentioning

confidence: 99%

Mechanism of Inhibition of Vaccinia Virus DNA Polymerase by Cidofovir Diphosphate

Magee

Hostetler

Evans

2005

Antimicrob Agents Chemother

140

150

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Cidofovir (CDV) is a broad-spectrum antiviral agent that has been approved for clinical use in the treatment of cytomegalovirus retinitis. It has also been used off label to treat a variety of other viral infections, including those caused by orf and molluscum contagiosum poxviruses. Because it is a dCMP analog, CDV is thought to act by inhibiting viral DNA polymerases. However, the details of the inhibitory mechanism are not well established and nothing is known about the mechanism by which the drug inhibits poxvirus DNA polymerases. To address this concern, we have studied the effect of the active intracellular metabolite of CDV, CDV diphosphate (CDVpp), on reactions catalyzed by vaccinia virus DNA polymerase. Using different primertemplate pairs and purified vaccinia virus polymerase, we observed that CDV is incorporated into the growing DNA strand opposite template G's but the enzyme exhibits a lower catalytic efficiency compared with dCTP. CDV-terminated primers are also good substrates for the next deoxynucleoside monophosphate addition step, but these CDV ؉ 1 reaction products are poor substrates for further rounds of synthesis. We also noted that although CDV can be excised from the primer 3 terminus by the 3-to-5 proofreading exonuclease activity of vaccinia virus polymerase, DNAs bearing CDV as the penultimate 3 residue are completely resistant to exonuclease attack. These results show that vaccinia virus DNA polymerase can use CDVpp as a dCTP analog, albeit one that slows the rate of primer extension. By inhibiting the activity of the proofreading exonuclease, the misincorporation of CDV could also promote error-prone DNA synthesis during poxvirus replication.Poxviruses are large, double-stranded DNA viruses that replicate in the cytoplasm of infected cells. Members of this virus family can cause severe infections, including human smallpox. Smallpox was declared eradicated in 1980, but concerns over bioterrorism (12,27) and a recent outbreak of monkeypox in the midwestern United States (19) illustrate some need for the continued development of effective new treatment regimens. A number of new treatments are currently the subject of active investigation, including immunotherapy. However, antiviral drugs offer a combination of chemical stability and simplicity of delivery that is especially attractive from a public health perspective.One class of drugs that have been shown to inhibit poxvirus replication are the nucleoside phosphonate analogs of cellular deoxyribonucleotides that were developed by De Clercq et al. (9). These drugs have been shown to be effective against a wide range of DNA viruses and retroviruses (reviewed in reference 8), and one of these compounds, (S)-1-[3-hydroxy-2-(phosphonylmethoxypropyl)]cytosine, also known as cidofovir (CDV), has been granted Food and Drug Administration approval for the treatment of cytomegalovirus (CMV)-induced retinitis. CDV has been used off label in the treatment of orf (11) and molluscum contagiosum (21) virus infections. It has also been shown to block ...

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Mechanism of Inhibition of Vaccinia Virus DNA Polymerase by Cidofovir Diphosphate

Magee

Hostetler

Evans

2005

Antimicrob Agents Chemother

140

150

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“…Cidofovir (1-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl] cytosine; CDV) is an acyclic phosphonate analog of cytosine that has been shown to have activity against all doublestranded DNA viruses studied to date, including herpes group viruses, orthopoxviruses, parapoxviruses, adenoviruses, and papovaviruses (De Clercq et al, 1987;Snoeck et al, 1988;De Clercq, 1997). CDV (Vistide; Gilead Sciences, Foster City, CA) is approved as an intravenous treatment for cytomegalovirus retinitis in AIDS patients but has doselimiting renal side effects (Lea and Bryson, 1996;Plosker and Noble, 1999).…”

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Increased Antiviral Activity of 1-O-Hexadecyloxypropyl-[2-¹⁴C]cidofovir in MRC-5 Human Lung Fibroblasts Is Explained by Unique Cellular Uptake and Metabolism

et al. 2003

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Recently, there has been renewed interest in finding orally active drugs against smallpox. Cidofovir (CDV) given by parenteral injection has been shown to protect against lethal poxvirus infection. We have been interested in the synthesis and evaluation of orally active derivatives of CDV. Previous studies showed that the CDV and cyclic cidofovir (cCDV) analogs 1-Ohexa-decyloxypropyl-CDV (HDP-CDV) and 1-O-hexadecyloxypropyl-cCDV (HDP-cCDV), show Ͼ100-fold increases in antiviral activity versus the unmodified nucleosides against cells infected with orthopoxviruses, cowpox, and vaccinia virus. In contrast to CDV, HDP-CDV is orally bioavailable and has been reported to be orally active in lethal cowpox virus infection in mice. To assess the metabolic basis for the increased antiviral activity of HDP-CDV in vitro, we studied the cellular uptake and anabolic metabolism of 14 C-labeled CDV, cCDV, and their alkoxyalkanol esters HDP-CDV and HDP-cCDV. HDP-CDV and HDP-cCDV were taken up rapidly by MRC-5 human lung fibroblasts in vitro, but uptake of CDV and cCDV was much slower. Analysis of cellular metabolites showed that levels of cidofovir diphosphate (CDV-DP), the active antiviral compound, were Ͼ100 times greater with HDP-CDV than levels observed with CDV. When cells were exposed to HDP-CDV, the intracellular half-life of CDV-DP was 10 days versus 2.7 days reported when cells are exposed to CDV. HDP-CDV seems to circumvent poor cellular uptake by rapid association with cellular membrane phospholipids, whereas CDV uptake proceeds via the slow process of fluid endocytosis.

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“…Potential nephrotoxicity (27) and poor oral bioavailability (14), however, may limit its widespread use in the event of a smallpox outbreak. The inhibitory effect of another ANP, PMEA, against retro-, herpes-and hepadnaviruses has been demonstrated (18,36). The low oral bioavailability in animals and humans (14) of this compound, which is a common feature of ANPs, led to the development of an oral prodrug, adefovir dipivoxil [bis(pivaloyl)oxymethyl PMEA], which was recently approved for treatment of hepatitis B (M. B. McClellan, Letter, JAMA 288:2112, 2002).…”

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

Keith

Hitchcock

Lee

et al. 2003

Antimicrob Agents Chemother

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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 (EC 50 s) from 4 to 8 M, compared with 33 to 43 M 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 EC 50 s of 0.1 to 2.6 M. 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.The success of the acyclic nucleoside phosphonate analogs (ANPs) as broad-spectrum antiviral agents with potent and selective activity in vitro and in vivo is the result of selective interactions of their diphosphate metabolite, which acts as both a competitive inhibitor and an alternative substrate with the viral DNA polymerase. The prototype compounds for this class of agents are (S)-1-[3-hydroxy-2-(phosphonomethoxy) propyl]cytosine (HPMPC) (also known as cidofovir [CDV]), 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) (also known as adefovir), and (R)-9-[2-(phosphonomethoxy) propyl]adenine (PMPA) (also known as tenofovir). CDV, which is the best-known member of this class of compounds, and its cyclic ester cHPMPC have potent and prolonged in vitro and in vivo activity against several herpesviruses, including herpes simplex virus types 1 and 2, varicella-zoster virus, cytomegalovirus, and Epstein-Barr virus (16,17,28). CDV is currently approved for treatment of cytomegalovirus retinitis in patients with AIDS (26, 32). In addition, CDV is a potent inhibitor of poxvirus replication in vitro (24,25,35) and has been shown to be very effective against both vaccinia virus (VV) and cowpox virus (CV) infections in animal models

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Acyclic Nucleoside Phosphonates in the Chemotherapy of DNA Virus and Retrovirus Infections

Cited by 72 publications

References 17 publications

Mechanism of Inhibition of Vaccinia Virus DNA Polymerase by Cidofovir Diphosphate

Mechanism of Inhibition of Vaccinia Virus DNA Polymerase by Cidofovir Diphosphate

Increased Antiviral Activity of 1-O-Hexadecyloxypropyl-[2-¹⁴C]cidofovir in MRC-5 Human Lung Fibroblasts Is Explained by Unique Cellular Uptake and Metabolism

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

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Acyclic Nucleoside Phosphonates in the Chemotherapy of DNA Virus and Retrovirus Infections

Cited by 72 publications

References 17 publications

Mechanism of Inhibition of Vaccinia Virus DNA Polymerase by Cidofovir Diphosphate

Mechanism of Inhibition of Vaccinia Virus DNA Polymerase by Cidofovir Diphosphate

Increased Antiviral Activity of 1-O-Hexadecyloxypropyl-[2-14C]cidofovir in MRC-5 Human Lung Fibroblasts Is Explained by Unique Cellular Uptake and Metabolism

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

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Increased Antiviral Activity of 1-O-Hexadecyloxypropyl-[2-¹⁴C]cidofovir in MRC-5 Human Lung Fibroblasts Is Explained by Unique Cellular Uptake and Metabolism