Acyclovir Monophosphate Research Articles

Acyclovir phosphoramidates as potential anti-HIV drugs

A number of phosphoramidate derivatives of acyclovir (ACV) were obtained. These compounds revealed themselves as latent forms of acyclovir monophosphate (ACV-MP). The optimized route to the title phosphoramidates involves the synthesis of intermediate phosphorodichloridates followed by their treatment with various amines. The compounds obtained showed moderate antiviral activity both in vitro in a controlled system of secure screening for anti-HIV agents and in a tissue system enabling ex vivo determination of the efficiency of the drug and its effect on HIV replication in two weeks.

Turning an antiviral into an anticancer drug: Nanoparticle delivery of acyclovir monophosphate

Anti-herpes simplex virus (HSV) drug acyclovir (ACV) is phosphorylated by the viral thymidine kinase (TK), but not the cellular TK. Phosphorylated ACV inhibits cellular DNA synthesis and kills the infected cells. We hypothesize that ACV monophosphate (ACVP), which is an activated metabolite of ACV, should be efficient in killing cells independent of HSV-TK. If so, ACVP should be a cytotoxic agent if properly delivered to the cancer cells. The Lipid/Calcium/Phosphate (LCP) nanoparticles (NPs) with a membrane/core structure were used to encapsulate ACVP to facilitate the targeted delivery of ACVP to the tumor. The LCP NPs showed entrapment efficiency of ~70%, the nano-scaled particle size and positive zeta potential. Moreover, ACVP-loaded LCP NPs (A-LCP NPs) exhibited concentration-dependent cytotoxicity against H460 cells and increased S-phase arrest. More importantly, a significant reduction of the tumor volume over 4days following administration (p<0.05–0.005) of A-LCP NPs, suggests excellent in vivo efficacy. Whereas, two free drugs (ACV and ACVP) and blank LCP NPs showed little or no therapeutic effect. It was also found that the high efficacy of A-LCP NPs was associated with the ability to induce dramatic apoptosis of the tumor cells, as well as significantly inhibit tumor cell proliferation and cell cycle progression. In conclusion, with the help of LCP NPs, monophosphorylation modification of ACV can successfully modify an HSV-TK-dependent antiviral drug into an anti-tumor drug.

Turning an antiviral into an anticancer drug: Nanoparticle delivery of acyclovir monophosphate

Turning an antiviral into an anticancer drug: Nanoparticle delivery of acyclovir monophosphate

Consistent Inhibition of HIV-1 Replication in CD4 + T Cells by Acyclovir without Detection of Human Herpesviruses

Acyclovir, a nucleoside analog, is thought to be specific for the human herpesviruses because it requires a virally encoded enzyme to phosphorylate it to acyclovir monophosphate. Recently, acyclovir triphosphate was shown to be a direct inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. Here, we showed that acyclovir is an inhibitor of HIV-1 replication in CD4(+) T cells from cord blood that have undetectable levels of the eight human herpesviruses. Additionally, acyclovir phosphates were detected by reverse-phase-high performance liquid chromatography (RP-HPLC) and quantified in a primer extension assay from cord blood. The data support acyclovir as an inhibitor of HIV-1 replication in herpesvirus-negative cells.

Mechanisms Associated with HIV-1 Resistance to Acyclovir by the V75I Mutation in Reverse Transcriptase

It has recently been demonstrated that the anti-herpetic drug acyclovir (ACV) also displays antiviral activity against the human immunodeficiency virus type 1 (HIV-1). The triphosphate form of ACV is accepted by HIV-1 reverse transcriptase (RT), and subsequent incorporation leads to classical chain termination. Like all approved nucleoside analogue RT inhibitors (NRTIs), the selective pressure of ACV is associated with the emergence of resistance. The V75I mutation in HIV-1 RT appears to be dominant in this regard. By itself, this mutation is usually not associated with resistance to currently approved NRTIs. Here we studied the underlying biochemical mechanism. We demonstrate that V75I is also selected under the selective pressure of a monophosphorylated prodrug that was designed to bypass the bottleneck in drug activation to the triphosphate form (ACV-TP). Pre-steady-state kinetics reveal that V75I discriminates against the inhibitor at the level of catalysis, whereas binding of the inhibitor remains largely unaffected. The incorporated ACV-monophosphate (ACV-MP) is vulnerable to excision in the presence of the pyrophosphate donor ATP. V75I compromises binding of the next nucleotide that can otherwise provide a certain degree of protection from excision. Collectively, the results of this study suggest that ACV is sensitive to two different resistance pathways, which warrants further investigation regarding the detailed resistance profile of ACV. Such studies will be crucial in assessing the potential clinical utility of ACV and its derivatives in combination with established NRTIs.

Cell Metabolism of Acyclovir Phosphonate Derivatives and Antiherpesvirus Activity of their Combinations with α2‐Interferon

The combinational use of acyclovir (ACV) phosphonate esters and alpha(2)-interferon was shown to produce a synergistic effect on inhibition of HSV-1 replication in Vero cell cultures. Unlike other acyclovir phosphonate derivatives studied earlier, ACV H-phosphonate is not an ACV prodrug. On penetrating into the cells, it may be directly converted into ACV monophosphate escaping dephosphonylation-phosphorylation steps.

The role of a HSV thymidine kinase stimulating substance, scopadulciol, in improving the efficacy of cancer gene therapy

The most extensively investigated strategy of suicide gene therapy for treatment of cancer is the transfer of the herpes simplex virus thymidine kinase (HSV-TK) gene followed by administration of antiviral prodrugs such as acyclovir (ACV) and ganciclovir (GCV). The choice of the agent that can stimulate HSV-TK enzymatic activity is one of the determinants of the usefulness of this strategy. Previously, we found that a diterpenoid, scopadulciol (SDC), produced a significant increase in the active metabolite of ACV. This suggests that SDC may play a role in the HSV-TK/prodrug administration system. The anticancer effect of SDC was evaluated in HSV-TK-expressing (TK+) cancer cells and nude mice bearing TK+ tumors. In vitro and in vivo enzyme assays were performed using TK+ cells and tumors. The phosphorylation of ACV monophosphate (ACV-MP) was measured in TK- cell lysates. The pharmacokinetics of prodrugs was evaluated by calculating area-under-the-concentration-time-curve values. SDC stimulated HSV-TK activity in TK+ cells and tumors, and increased GCV-TP levels, while no effect of SDC was observed on the phosphorylation of ACV-MP to ACV-TP by cellular kinases. The SDC/prodrug combination altered the pharmacokinetics of the prodrugs. In accord with these findings, SDC enhanced significantly the cell-killing activity of prodrugs. The bystander effect was also significantly augmented by the combined treatment of ACV/GCV and SDC. SDC was shown to be effective in the HSV-TK/prodrug administration system and improved the efficiency of the bystander effect of ACV and GCV. The findings will be considerably valuable with respect to the use of GCV in lower doses and less toxic ACV. This novel strategy of drug combination could provide benefit to HSV-TK/prodrug gene therapy.

Antiviral activities of oral 1-O-hexadecylpropanediol-3-phosphoacyclovir and acyclovir in woodchucks with chronic woodchuck hepatitis virus infection.

Acyclovir triphosphate is a potent inhibitor of hepatitis B virus DNA polymerase, but acyclovir treatment provides no benefit in patients with hepatitis B virus infection. This is due in part to the fact that hepatitis B virus, unlike herpes simplex virus, does not code for a viral thymidine kinase which catalyzes the initial phosphorylation of acyclovir. We synthesized 1-O-octadecyl-sn-glycero-3-phospho (3-P)-acyclovir and found that it was highly active in reducing hepatitis B virus replication in 2.2. 15 cells, while acyclovir was inactive. The greater antiviral activity of 1-O-octadecyl-sn-glycero-3-P-acyclovir appeared to be due to liver cell metabolism of the compound to acyclovir monophosphate (K. Y. Hostetler et al., Biochem. Pharmacol. 53:1815-1822, 1997). However, a closely related compound without a hydroxyl group at the sn-2 position of glycerol, 1-O-hexadecylpropanediol-3-P-acyclovir, was more active and selective in 2.2.15 cells in vitro. In this study, we treated woodchucks chronically infected with woodchuck hepatitis virus with increasing oral doses of 1-O-hexadecylpropanediol-3-P-acyclovir and assessed the response to therapy versus acyclovir or a placebo. At a dosage of 10 mg/kg of body weight twice a day, the test compound significantly inhibited viral replication in vivo, as indicated by a 95% reduction in serum woodchuck hepatitis virus DNA levels and by a 54% reduction in levels of woodchuck hepatitis virus replicative intermediates in the liver. Higher doses were somewhat less effective. In contrast, 20 mg of acyclovir/kg twice daily, a 5. 3-fold-higher molar dosage, had no demonstrable activity against woodchuck hepatitis virus. Oral 1-O-hexadecylpropanediol-3-P-acyclovir appeared to be safe and effective in chronic woodchuck hepatitis virus infection.

Efficacy of Topical Acyclovir Monophosphate, Acyclovir, or Penciclovir in Orofacial HSV-1 Infections of Mice and Genital HSV-2 Infections of Guinea Pigs

The purpose of these studies was to compare the efficacy of acyclovir monophosphate (ACVMP), acyclovir (ACV), or penciclovir (PCV) against HSV-1 in an orofacial infection of mice and against ACV sensitive and resistant genital HSV-2 infections of guinea pigs. Treatment was initiated 24, 48, or 72 hours post inoculation with 5% ACVMP, 5% ACV (Zovirax) or 1% PCV (Denavir). In all experiments, similar efficacy was obtained for ACVMP and ACV, whereas PCV was considerably less effective.

Synthesis, Biological Activity and Decomposition Studies of Amino Acid Phosphomonoester Amidates of Acyclovir

Highly stable and water soluble amino acid phosphomonoester amidates of acyclovir (ACV) were synthesized and shown to function predominantly as prodrugs of AC V and not acyclovir monophosphate (AC V-MP) with activities within two fold of the amino acid prodrug of ACV, valaciclovir (VACV). Metabolism studies revealed that incubation of cell-free extracts of Vero cells with the L-leucine phosphomonoester amidate of ACV (3c), resulted in a burst of ACV-MP production followed by the rapid generation of ACV.

Heterogeneous response for a mammalian hepadnavirus infection to acyclovir: Drug-arrested intermediates of minus-strand viral DNA synthesis are enveloped and secreted from infected cells as virion-like particles

Three woodchucks infected persistently with the woodchuck hepatitis virus (WHV) were treated with acyclovir (ACV) to investigate the effect of inhibiting viral DNA synthesis upon the replication of an orthohepadnavirus in vivo. Normal viraemia was reduced during the treatment period in all three animals, but each responded with a distinct serum phenotype. In the most provocative case, the profile of the WHV DNAs in both the liver and serum provided a simple and novel description of the orthohepadnaviral infection for this ACV protocol. The pre-drug viraemia was rapidly cleared from the serum and replaced by virion-like particles containing predominantly minus-strand WHV DNAs. These serum DNA species had the character of replicative intermediates arrested in their elongation by ACV-mediated chain termination and were contained in particles with a buoyant density in CsCl essentially identical with virions. However, in infected hepatocytes, initiation of reverse transcription within newly formed core particles was not inhibited by the ACV treatment. Instead, an heterogeneous array of minus-strand DNAs were synthesised, each presumed to be truncated by the incorporation of one molecule of ACV monophosphate. An approximately normal level of core particles was present in the liver of this woodchuck after 26 days of the ACV protocol; excess drug-arrested nucleocapsids were steadily removed throughout the dosing period upon their envelopment and secretion as virion-like particles into the circulation. These data suggest that plus-strand DNA synthesis may not be absolutely required prior to secretion of virus from the infected cell.

The crystal structure and characterization of a copper(II) complex with a guanosine-5′-monophosphate analog (acyclovir monophosphate)

The synthesis of the coordination compound [Cu(acvmp) 2(H 2O) ( I) (acvmp = acyclovir monophosphate) is reported. Its crystal structure is presented and discussed. The title compound crystallizes in the triclinic space group P 1 with a = 8.556(2), b = 9.697(2), c = 9.951(2) A ̊ , α = 63.96(3), β = 67.23(3), γ = 68.04(3) 0, V = 662.9(2) A ̊ 3, Z = 1, D c = 1.771 g/cm 3 . There is a distorted octahedral coordination around copper(II) in the title compound. The copper atom occupying the center of inversion is coordinated to N(7) (2.067(4) Å) and to the oxygen of a water molecule ( Cu(1)—O(1W) = 1.962(3) A ̊ ). Additionally, the oxygen of the phosphate group belonging to the next acvmp molecule is coordinated to copper(II) in the axial position ( Cu(1)—O(1) ii = 2.390(4) A ̊ ). This type of bonding leads to a polymeric structure extending through the crystal. The results of different other physical measurement (TG, FT-IR) are also included.

Valacyclovir

Valacyclovir is the l-valyl ester prodrug of acyclovir and exhibits similar potency, but has more favorable pharmacokinetic characteristics, requiring a less frequent dosing schedule and achieving higher blood plasma levels than acyclovir. With the acyclovir prodrugs, the physical properties such as water or lipid solubilities (log P) are not major determinants of the most effective bioavailability. The structure-activity relationship of the amino acid esters suggests the involvement of a stereospecific transport process. The common branched chain amino acids, l-valine and l-isoleucine, are favored by this proposed transporter. 2 Acyclovir is a derivative of guanosine. A critical step in its activation is phosphorylation by viral thymidine kinase. The affinity of acyclovir for herpes virus-encoded thymidine kinase is approximately 200 times greater than for human thymidine kinase, and phosphorylation of acyclovir by the human enzyme occurs at a negligible rate. This selective affinity results in the activation and concentration of acyclovir in virus-infected cells. After phosphorylation to acyclovir monophosphate (acyclo-GMP), normal cellular enzymes catalyze the sequential phosphorylation to acyclovir diphosphate (acyclo-GDP) and acyclovir triphosphate (acyclo-GTP). Acyclovir triphosphate terminates the production of viral DNA by inhibiting DNA polymerase via competition with deoxyguanosine triphosphate; it has selective affinity for viral DNA polymerase. In addition, acyclo-GTP is incorporated into the elongating viral DNA, where it causes termination of the viral DNA strand. 3,4,5 After oral administration, valacyclovir is rapidly absorbed and extensively converted to acyclovir via first-pass metabolism. Acyclovir has been detected in plasma as early as 15 min after the valacyclovir administration. Oral administration results in plasma acyclovir concentrations approximately 3- to 5-fold greater than those achievable with comparable oral doses of acyclovir. 6,7,8 The elimination half-life of acyclovir is approximately 3 h; acyclovir is primarily excreted unchanged in the urine. Valacyclovir appears to be a significant development in antiviral therapy. Its significantly greater oral bioavailability results in plasma acyclovir levels comparable to those seen with intravenous acyclovir. Although acyclovir has been effective in immunocompetent patients with mucocutaneous herpes simplex virus (HSV) infection, the need for multiple daily dosing has been problematic. With a higher C max after valacyclovir administration, less frequent dosing may be equally effective, both for acute treatment and for suppression. In the treatment of recurrent genital herpes simplex infections, valacyclovir 1,000 mg orally twice a day for 5 days has been effective. In patients receiving the drug within 24 h of initiation of signs and symptoms, valacyclovir was as effective as acyclovir in reducing time to lesion healing and length of episode. 9 Herpes zoster (shingles) patients treated with oral valacycyclovir report complete cessation of postherpetic pain in a statistically shorter time than patients treated with oral acyclovir; the two drugs have a similar time to rash healing. Valacyclovir has been approved for marketing in the U.S.A. as a treatment for shingles in immunocompetent patients. Valacyclovir was first launched in the U.K. and Ireland in January 1995, and has since been launched in Sweden.

Acyclovir diphosphate dimyristoylglycerol: a phospholipid prodrug with activity against acyclovir-resistant herpes simplex virus.

Infection with herpes simplex viruses (HSVs) resistant to treatment with acyclovir (9-[(2-hydroxyethoxy)-methyl]guanine, Zovirax) is a growing clinical problem in patients with AIDS and other immunosuppressed states. Most virus isolates resistant to acyclovir are deficient or defective in virally coded thymidine kinase (TK), which converts acyclovir to acyclovir monophosphate in virus-infected cells. To restore acyclovir efficacy, we synthesized acyclovir diphosphate dimyristoylglycerol, an analog of a naturally occurring phospholipid, CDP-diacylglycerol. Its biological activity was tested in WI38 human lung fibroblasts infected with the acyclovir-resistant DM21 strain of HSV, which is TK negative due to an 816-base-pair deletion in the TK coding region. Acyclovir diphosphate dimyristoylglycerol has substantial activity in DM21-infected cells (IC50 = 0.25 microM), whereas acyclovir and acyclovir monophosphate were ineffective (IC50 > 100 microM). Similar results were obtained in TK-altered and TK-deficient strains of HSV-1 and in acyclovir-resistant isolates of HSV-2 obtained from two AIDS patients. The phospholipid prodrug is active by means of TK-independent metabolic pathways that liberate acyclovir monophosphate inside the host cell. Acyclovir phosphates were 56 times greater in WI38 human lung fibroblasts incubated for 24 hr with [8-3H]acyclovir diphosphate dimyristoylglycerol relative to acyclovir. Acyclovir monophosphate added to the culture medium (outside the cell) did not circumvent the acyclovir resistance of the TK-negative DM21 mutant, presumably due to its conversion to acyclovir by phosphatases. Acyclovir diphosphate diacylglycerol prodrugs may be useful in treating TK-deficient mutant and wild-type strains of HSV.

SDZ-HSV-863: A human monoclonal antibody to HSV-1 and HSV-2 (gD-Ib) which attenuates acute infection, neurogenic cutaneous lesion formation and the establishment of viral latency : Lake, P., Alonso, A., Subramanyam, J. and Nottage, B. Department of Cellular Pharmacology, Sandoz Research Institute, E. Hanover, NJ, U.S.A.

Anti-herpes simplex virus (HSV) drug acyclovir (ACV) is phosphorylated by the viral thymidine kinase (TK), but not the cellular TK. Phosphorylated ACV inhibits cellular DNA synthesis and kills the infected cells. We hypothesize that ACV monophosphate (ACVP), which is an activated metabolite of ACV, should be efficient in killing cells independent of HSV-TK. If so, ACVP should be a cytotoxic agent if properly delivered to the cancer cells. The Lipid/Calcium/Phosphate (LCP) nanoparticles (NPs) with a membrane/core structure were used to encapsulate ACVP to facilitate the targeted delivery of ACVP to the tumor. The LCP NPs showed entrapment efficiency of ~ 70%, the nano-scaled particle size and positive zeta potential. Moreover, ACVP-loaded LCP NPs (A-LCP NPs) exhibited concentration-dependent cytotoxicity against H460 cells and increased S-phase arrest. More importantly, a significant reduction of the tumor volume over 4 days following administration (p < 0.05–0.005) of A-LCP NPs, suggests excellent in vivo efficacy. Whereas, two free drugs (ACV and ACVP) and blank LCP NPs showed little or no therapeutic effect. It was also found that the high efficacy of A-LCP NPs was associated with the ability to induce dramatic apoptosis of the tumor cells, as well as significantly inhibit tumor cell proliferation and cell cycle progression. In conclusion, with the help of LCP NPs, monophosphorylation modification of ACV can successfully modify an HSV-TK-dependent antiviral drug into an anti-tumor drug.

Adenine arabinoside monophosphate and acyclovir monophosphate coupled to lactosaminated albumin reduce woodchuck hepatitis virus viremia at doses lower than do the unconjugated drugs

The woodchuck was selected to study the efficacy of liver-targeted antiviral drugs on hepadnavirus replication. Nineteen woodchucks chronically infected with woodchuck hepatitis virus were treated with adenine arabinoside monophosphate or acyclovir monophosphate, either free or conjugated with the liver-targeting molecule lactosaminated human serum albumin. Circulating woodchuck hepatitis virus DNA levels remained unchanged in untreated animals and in those receiving the carrier lactosaminated human serum albumin alone; in contrast, they were consistently lower after 5 days of treatment with the antiviral drugs. Free and conjugated adenine arabinoside monophosphate were active at doses of 10 and 0.75 mg/kg, respectively, and free and coupled ACVMP were active at doses of 20 and 2.6 mg/kg, respectively. These results indicate that the dosages of adenine arabinoside monophosphate and acyclovir monophosphate required to inhibit hepadnavirus growth can be sharply reduced by coupling the drugs to lactosaminated human serum albumin.

Antiviral agents for hepatitis B

HepatologyVolume 14, Issue 1 p. 198-199 EditorialFree Access Antiviral agents for hepatitis B John L. Gerin Ph.D., Corresponding Author John L. Gerin Ph.D. Division of Molecular Virology and Immunology Georgetown University Medical Center Rockville, Maryland 20852Georgetown University, 5640 Fishers Lane, Rockville, MD 20852===Search for more papers by this author John L. Gerin Ph.D., Corresponding Author John L. Gerin Ph.D. Division of Molecular Virology and Immunology Georgetown University Medical Center Rockville, Maryland 20852Georgetown University, 5640 Fishers Lane, Rockville, MD 20852===Search for more papers by this author First published: July 1991 https://doi.org/10.1002/hep.1840140132Citations: 9AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. References 1 Ponzetto A, Forzani B, Busi C, Spinelli S, Smedile A, Bonino F, Verme G. Adenine arabinoside monophosphate and acyclovir monophosphate coupled to lactosaminated albumin inhibit woodchuck hepatitis virus replication at low doses. HEPATOLOGY 1991; 14: 16– 23. 2 Pollard RB, Smith JL, Beal A, Gregory PB, Merigan TC, Robinson WS. Effect of vidarabine on chronic hepatitis B infection. JAMA 1978; 239: 1648. 3 Hoofnagle JH, Hanson RG, Minuk GY, Pappas SC, Schafer DF, Dusheiko GM, Straus SE, et al. Randomized controlled trial of adenine arabinoside monophosphate for chronic type B hepatitis. Gastroenterology 1984; 86: 150– 157. 4 Weller IVD, Lok ASF, Mindel A, Karayiannis P, Galpin S, Monjardino J, Sherlock S, et al. Randomized controlled trial of adenine arabinoside 5′-monophosphate (ara-AMP) in chronic hepatitis B virus infection. Gut 1985; 26: 745– 751. 5 Lok ASF, Wilson LA, Thomas HC. Neurotoxicity associated with adenine arabinoside monophosphate in the treatment of chronic hepatitis B virus infection. J Antimicrob Chemother 1984; 14: 93– 99. 6 Perrillo RP. Treatment of chronic hepatitis B with interferon: experience in Western countries. Semin Liver Dis 1989; 9: 240– 248. 7 Scullard GH, Andress LL, Greenberg HB, Smith JL, Sawhney VK, Neal EA, Mahal AS, et al. Antiviral treatment of chronic hepatitis B virus infection: improvement in liver disease with interferon and adenine arabinoside. HEPATOLOGY 1981; 1: 228– 232. 8 Robinson WS. Hepadnaviridae and their replication. In: Hollinger FB, Robinson WS, Purcell RH. Viral Hepatitis, 2nd Edition, Raven Press, New York, 1991; p. 39– 71. 9 Fiume L, Busi C, Mattioli A, Spinosa G. Targeting of antiviral drugs bound to protein carriers. Crit Ther Drug Carrier Sys 1988; 4: 265– 284. 10 Fiume L, Torrani-Cerenzia MR, Bonino F, Busi C, Mattioli A, Brunetto MR, Chiaberge E, et al. Inhibition of hepatitis B virus replication by vidarabine monophosphate conjugated with lactosaminated serum albumin. Lancet 1988; 2: 13– 15. 11 Hirota K, Sherker AH, Omata M, Yokosuka O, Okuda K. Effects of adenine arabinoside on serum and intrahepatic replicative forms of duck hepatitis B virus in chronic infection. HEPATOLOGY 1987; 7: 24– 28. 12 Petcu DJ, Aldrich CE, Coates L, Taylor JM, Mason WS. Suramin inhibits in vitro infection by duck hepatitis B virus, Rous sarcoma virus, and hepatitis delta virus. Virology 1988; 167: 385– 392. 13 Gerin JL, Cote PJ, Korba BE, Tennant BC. Hepadnavirus-induced liver cancer in woodchucks. Cancer Detect Prev 1989; 14: 227– 229. 14 Tennant BC, Hornbuckle WE, Baldwin BH, King JM, Cote P, Popper H, Purcell RH, et al. Influence of age on the response to experimental woodchuck hepatitis virus infection. In: AJ Zuckerman, ed. Viral hepatitis and liver disease New York: Alan R. Liss, Inc., 1988: 462– 464. 15 Korba BE, Cote PJ, Wells FV, Baldwin B, Cote PJ, Tennant BC, Popper H, et al. Natural history of WHV infections during the course of experimental viral infection: molecular virologic features of the liver and lymphoid tissues. J Virol 1989; 63: 1360– 1370. Citing Literature Volume14, Issue1July 1991Pages 198-199 ReferencesRelatedInformation

A new class of acyclic phosphonate nucleotide analogues: phosphonate isosteres of acyclovir and ganciclovir monophosphates as antiviral agents.

Novel phosphonate isosteres of acyclovir (ACV) and ganciclovir (DHPG) monophosphates were found to be potent and selective antiherpesvirus agents. In the series of phosphonate analogues of ACV monophosphate, only the guanine analogue 20 exhibited activity against herpesviruses, similar to the structure-activity relationship observed for base modification of ACV analogues. The phosphonate isostere of ACV monophosphate (20) was more effective than ACV in the HSV-1 infected mouse model. The 3'-carba analogues of 9-[3-hydroxy-2-(phosphonomethoxy)propyl]purines/pyrimidines (adenine, HPMPA; guanine, HPMPG; cytosine, HPMPC) are devoid of antiherpesvirus activity. This result confirms that the beta-oxygen atom of the phosphonomethyl ether functionality in HPMP-purines/pyrimidines plays a critical role for activity against herpesviruses.

ChemInform Abstract: Synthesis of a Phosphonate Isostere of Acyclovir Monophosphate: A Herpesvirus Active Phosphonate Nucleotide Analogue.

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Herpes simplex virus type 1 DNA polymerase. Mechanism-based affinity chromatography.

The potent inhibition of herpes simplex type 1 (HSV-1) DNA polymerase by acyclovir triphosphate has previously been shown to be due to the formation of a dead-end complex upon binding of the next 2'-deoxynucleoside 5'-triphosphate encoded by the template after incorporation of acyclovir monophosphate into the 3'-end of the primer (Reardon, J. E., and Spector, T. (1989) J. Biol. Chem. 264, 7405-7411). This mechanism of inhibition of HSV-1 DNA polymerase has been used here to design an affinity column for the enzyme. A DNA hook template-primer containing an acyclovir monophosphate residue on the 3'-primer terminus has been synthesized and attached to a resin support. In the absence of added nucleotides, the column behaves as a simple DNA-agarose column, and HSV-1 DNA polymerase can be chromatographed using a salt gradient. The presence of the next required nucleotide encoded by the template (dGTP) increases the affinity of HSV-1 DNA polymerase for the acyclovir monophosphate terminal primer-template attached to the resin, and the enzyme is retained even in the presence of 1 M salt. The enzyme can be eluted from the column with a salt gradient after removal of the nucleotide from the buffer. Traditionally, the affinity purification of an enzyme relies on elution by a salt gradient, pH gradient, or more selectively by addition of a competing ligand (substrate/inhibitor) to the elution buffer. In the present example, elution of HSV-1 polymerase is facilitated by removal of the substrate from the buffer. This represents an example of mechanism-based affinity chromatography.