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  1. Article ; Online: A ProTide of AZT Shows Activity Against Human Papillomaviruses.

    Gniech, Tim / Humboldt, Adrian / Keith, Kathy A / James, Scott H / Richert, Clemens

    ChemMedChem

    2024  Volume 19, Issue 8, Page(s) e202300661

    Abstract: Infection by human papillomaviruses (HPV) can cause warts and tumors. So far, no small molecule antiviral has been approved for the treatment of infections with this DNA virus, although preclinical studies show activity for nucleosidic compounds, such as ...

    Abstract Infection by human papillomaviruses (HPV) can cause warts and tumors. So far, no small molecule antiviral has been approved for the treatment of infections with this DNA virus, although preclinical studies show activity for nucleosidic compounds, such as 9-(2-phosphonylmethoxy)ethylguanine (PMEG) or cidofovir. This prompted us to test new prodrug versions of the nucleoside analog 3'-azido-2',3'-dideoxythymidine (AZT), known to be active against reverse transcriptases and approved for the treatment of HIV. Here we report the synthesis of an ethylbutyl alaninyl ester phosphosphoramidate prodrug of AZT, dubbed AZAEB, and its activity against HPV, a target not known to be sensitive to AZT. A methyl ester derivative was found to be inactive against this and three other DNA viruses, while the phosphoramidate prodrug AZAEB showed a modest inhibitory effect against HPV types 6, 11, 18 and 31. Our results open up new avenues of study for the treatment of diseases caused by members of the papillomaviridae family.
    MeSH term(s) Humans ; Zidovudine/pharmacology ; ProTides ; Human Papillomavirus Viruses ; Papillomavirus Infections ; Nucleosides ; Prodrugs/pharmacology ; Esters ; Antiviral Agents/pharmacology
    Chemical Substances Zidovudine (4B9XT59T7S) ; ProTides ; Nucleosides ; Prodrugs ; Esters ; Antiviral Agents
    Language English
    Publishing date 2024-02-07
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 2218496-X
    ISSN 1860-7187 ; 1860-7179
    ISSN (online) 1860-7187
    ISSN 1860-7179
    DOI 10.1002/cmdc.202300661
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  2. Article ; Online: In Silico Design and Experimental Validation of Novel Oxazole Derivatives Against Varicella zoster virus.

    Kovalishyn, Vasyl / Severin, Oleksandr / Kachaeva, Maryna / Kobzar, Oleksandr / Keith, Kathy A / Harden, Emma A / Hartline, Caroll B / James, Scott H / Vovk, Andriy / Brovarets, Volodymyr

    Molecular biotechnology

    2023  Volume 66, Issue 4, Page(s) 707–717

    Abstract: Varicella zoster virus (VZV) infection causes severe disease such as chickenpox, shingles, and postherpetic neuralgia, often leading to disability. Reactivation of latent VZV is associated with a decrease in specific cellular immunity in the elderly and ... ...

    Abstract Varicella zoster virus (VZV) infection causes severe disease such as chickenpox, shingles, and postherpetic neuralgia, often leading to disability. Reactivation of latent VZV is associated with a decrease in specific cellular immunity in the elderly and in patients with immunodeficiency. However, due to the limited efficacy of existing therapy and the emergence of antiviral resistance, it has become necessary to develop new and effective antiviral drugs for the treatment of diseases caused by VZV, particularly in the setting of opportunistic infections. The goal of this work is to identify potent oxazole derivatives as anti-VZV agents by machine learning, followed by their synthesis and experimental validation. Predictive QSAR models were developed using the Online Chemical Modeling Environment (OCHEM). Data on compounds exhibiting antiviral activity were collected from the ChEMBL and uploaded in the OCHEM database. The predictive ability of the models was tested by cross-validation, giving coefficient of determination q
    MeSH term(s) Herpesvirus 3, Human/drug effects ; Oxazoles/chemistry ; Oxazoles/pharmacology ; Quantitative Structure-Activity Relationship ; Antiviral Agents/pharmacology ; Antiviral Agents/chemistry ; Antiviral Agents/chemical synthesis ; Humans ; Computer Simulation ; Drug Design ; Machine Learning
    Chemical Substances Oxazoles ; Antiviral Agents
    Language English
    Publishing date 2023-01-29
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 1193057-3
    ISSN 1559-0305 ; 1073-6085
    ISSN (online) 1559-0305
    ISSN 1073-6085
    DOI 10.1007/s12033-023-00670-w
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  3. Article ; Online: A standardized approach to the evaluation of antivirals against DNA viruses: Polyomaviruses and lymphotropic herpesviruses.

    Keith, Kathy A / Hartline, Caroll B / Bowlin, Terry L / Prichard, Mark N

    Antiviral research

    2018  Volume 159, Page(s) 122–129

    Abstract: The search for new compounds with a broad spectrum of antiviral activity is important and requires the evaluation of many compounds against several distinct viruses. Researchers attempting to develop new antiviral therapies for DNA virus infections ... ...

    Abstract The search for new compounds with a broad spectrum of antiviral activity is important and requires the evaluation of many compounds against several distinct viruses. Researchers attempting to develop new antiviral therapies for DNA virus infections currently use a variety of cell lines, assay conditions and measurement methods to determine in vitro drug efficacy, making it difficult to compare results from within the same laboratory as well as between laboratories. In this paper, we describe the assessment of antiviral activity of a set of nucleoside analogs against BK polyomavirus, JC polyomavirus, Epstein-Barr virus, human herpesvirus 6B, and human herpesvirus 8 in an automated 384-well format and utilize qPCR assays to measure the accumulation of viral DNA. In an accompanying paper, we present a standardized approach to evaluating antivirals against additional herpesviruses, orthopoxviruses, and adenovirus. Together, they reveal new activities for reference compounds and help to define the spectrum of antiviral activity for a set of nucleoside analogs against a set of 12 DNA viruses that infect humans including representative human herpesviruses, orthopoxviruses, adenoviruses, and polyomaviruses. This analysis helps provide perspective on combinations of agents that would help provide broad coverage of significant pathogens in immunocompromised patients as well as against emerging infections.
    MeSH term(s) Antiviral Agents/pharmacology ; Automation, Laboratory ; DNA, Viral/analysis ; Drug Discovery/methods ; Drug Discovery/standards ; Herpesviridae/drug effects ; Humans ; Nucleosides/pharmacology ; Polyomavirus/drug effects ; Virus Replication/drug effects
    Chemical Substances Antiviral Agents ; DNA, Viral ; Nucleosides
    Language English
    Publishing date 2018-10-01
    Publishing country Netherlands
    Document type Evaluation Study ; Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 306628-9
    ISSN 1872-9096 ; 0166-3542
    ISSN (online) 1872-9096
    ISSN 0166-3542
    DOI 10.1016/j.antiviral.2018.09.016
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  4. Article ; Online: A standardized approach to the evaluation of antivirals against DNA viruses: Orthopox-, adeno-, and herpesviruses.

    Hartline, Caroll B / Keith, Kathy A / Eagar, Jessica / Harden, Emma A / Bowlin, Terry L / Prichard, Mark N

    Antiviral research

    2018  Volume 159, Page(s) 104–112

    Abstract: The search for new compounds with a broad spectrum of antiviral activity is important and requires the evaluation of many compounds against several distinct viruses. Researchers attempting to develop new antiviral therapies for DNA virus infections ... ...

    Abstract The search for new compounds with a broad spectrum of antiviral activity is important and requires the evaluation of many compounds against several distinct viruses. Researchers attempting to develop new antiviral therapies for DNA virus infections currently use a variety of cell lines, assay conditions and measurement methods to determine in vitro drug efficacy, making it difficult to compare results from within the same laboratory as well as between laboratories. In this paper we describe a common assay platform designed to facilitate the parallel evaluation of antiviral activity against herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster virus, cytomegalovirus, vaccinia virus, cowpox virus, and adenovirus. The automated assays utilize monolayers of primary human foreskin fibroblast cells in 384-well plates as a common cell substrate and cytopathic effects and cytotoxicity are quantified with CellTiter-Glo. Data presented demonstrate that each of the assays is highly robust and yields data that are comparable to those from other traditional assays, such as plaque reduction assays. The assays proved to be both accurate and robust and afford an in depth assessment of antiviral activity against the diverse class of viruses with very small quantities of test compounds. In an accompanying paper, we present a standardized approach to evaluating antivirals against lymphotropic herpesviruses and polyomaviruses and together these studies revealed new activities for reference compounds. This approach has the potential to accelerate the development of broad spectrum therapies for the DNA viruses.
    MeSH term(s) Adenoviridae/drug effects ; Antiviral Agents/pharmacology ; Cells, Cultured ; Cytomegalovirus/drug effects ; Cytopathogenic Effect, Viral ; DNA Virus Infections/drug therapy ; Fibroblasts ; Herpesvirus 1, Human/drug effects ; Herpesvirus 2, Human/drug effects ; Herpesvirus 3, Human/drug effects ; Humans ; Orthopoxvirus/drug effects ; Viral Plaque Assay/standards
    Chemical Substances Antiviral Agents
    Language English
    Publishing date 2018-10-01
    Publishing country Netherlands
    Document type Evaluation Study ; Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 306628-9
    ISSN 1872-9096 ; 0166-3542
    ISSN (online) 1872-9096
    ISSN 0166-3542
    DOI 10.1016/j.antiviral.2018.09.015
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  5. Article ; Online: NPP-669, a Novel Broad-Spectrum Antiviral Therapeutic with Excellent Cellular Uptake, Antiviral Potency, Oral Bioavailability, Preclinical Efficacy, and a Promising Safety Margin.

    Lipka, Elke / Chadderdon, Aaron M / Harteg, Cheryl C / Doherty, Matthew K / Simon, Eric S / Domagala, John M / Reyna, Dawn M / Hutchings, Kim M / Gan, Xinmin / White, Andrew D / Hartline, Caroll B / Harden, Emma A / Keith, Kathy A / Prichard, Mark N / James, Scott H / Cardin, Rhonda D / Bernstein, David I / Spencer, Jacqueline F / Tollefson, Ann E /
    Wold, William S M / Toth, Karoly

    Molecular pharmaceutics

    2022  Volume 20, Issue 1, Page(s) 370–382

    Abstract: DNA viruses are responsible for many diseases in humans. Current treatments are often limited by toxicity, as in the case of cidofovir (CDV, Vistide), a compound used against cytomegalovirus (CMV) and adenovirus (AdV) infections. CDV is a polar molecule ... ...

    Abstract DNA viruses are responsible for many diseases in humans. Current treatments are often limited by toxicity, as in the case of cidofovir (CDV, Vistide), a compound used against cytomegalovirus (CMV) and adenovirus (AdV) infections. CDV is a polar molecule with poor bioavailability, and its overall clinical utility is limited by the high occurrence of acute nephrotoxicity. To circumvent these disadvantages, we designed nine CDV prodrug analogues. The prodrugs modulate the polarity of CDV with a long sulfonyl alkyl chain attached to one of the phosphono oxygens. We added capping groups to the end of the alkyl chain to minimize β-oxidation and focus the metabolism on the phosphoester hydrolysis, thereby tuning the rate of this reaction by altering the alkyl chain length. With these modifications, the prodrugs have excellent aqueous solubility, optimized metabolic stability, increased cellular permeability, and rapid intracellular conversion to the pharmacologically active diphosphate form (CDV-PP). The prodrugs exhibited significantly enhanced antiviral potency against a wide range of DNA viruses in infected human foreskin fibroblasts. Single-dose intravenous and oral pharmacokinetic experiments showed that the compounds maintained plasma and target tissue levels of CDV well above the EC
    MeSH term(s) Mice ; Humans ; Animals ; Antiviral Agents/pharmacokinetics ; Organophosphonates ; Biological Availability ; Prodrugs/pharmacology ; Cytosine ; Cidofovir ; Cytomegalovirus Infections
    Chemical Substances Antiviral Agents ; Organophosphonates ; Prodrugs ; Cytosine (8J337D1HZY) ; Cidofovir (JIL713Q00N)
    Language English
    Publishing date 2022-12-09
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2138405-8
    ISSN 1543-8392 ; 1543-8384
    ISSN (online) 1543-8392
    ISSN 1543-8384
    DOI 10.1021/acs.molpharmaceut.2c00668
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  6. Article: In vitro and in vivo evaluation of isatin-beta-thiosemicarbazone and marboran against vaccinia and cowpox virus infections.

    Quenelle, Debra C / Keith, Kathy A / Kern, Earl R

    Antiviral research

    2006  Volume 71, Issue 1, Page(s) 24–30

    Abstract: It has been reported previously that some thiosemicarbazone compounds have prophylactic activity against smallpox disease and therapeutic activity against vaccinia virus (VV) infections. In these studies, isatin-beta-thiosemicarbazone (IBT) and marboran ... ...

    Abstract It has been reported previously that some thiosemicarbazone compounds have prophylactic activity against smallpox disease and therapeutic activity against vaccinia virus (VV) infections. In these studies, isatin-beta-thiosemicarbazone (IBT) and marboran were administered once daily by intraperitoneal (ip) injection to mice using 30, 10 or 3 mg/kg for 5 days beginning 24, 48 or 72 h after inoculation with VV or cowpox virus (CV). Both compounds were highly effective (p < 0.01) at preventing mortality due to VV even when treatment was delayed up to 72 h postinfection. In CV-infected mice, neither IBT nor Marboran were effective in preventing mortality at any dosage tested when administered at 24 h postinoculation. Viral replication in liver, spleen and kidney was delayed or reduced by 100-to 10,000-fold by 10 mg/kg of marboran, but not IBT, in VV infections. Neither compound was effective against CV infection. Neither IBT nor marboran treatment of mice cutaneously infected with VV or CV reduced viral replication or clinical disease. These results suggest that this class of compound has little therapeutic potential for orthopoxvirus infections since the in vivo activity against CV, a surrogate virus for variola, is lacking.
    MeSH term(s) Animals ; Antibodies, Viral/blood ; Antiviral Agents/pharmacology ; Cowpox virus/physiology ; Female ; Hydrazones/pharmacology ; Indoles/pharmacology ; Methisazone/pharmacology ; Mice ; Mice, Hairless ; Mice, Inbred BALB C ; Poxviridae Infections/drug therapy ; Poxviridae Infections/virology ; Statistics, Nonparametric ; Survival Analysis ; Vaccinia virus/physiology ; Virus Replication/drug effects
    Chemical Substances Antibodies, Viral ; Antiviral Agents ; Hydrazones ; Indoles ; isatine-beta-thiocarbohydrazone ; Methisazone (K3QML4J07E)
    Language English
    Publishing date 2006-08
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 306628-9
    ISSN 1872-9096 ; 0166-3542
    ISSN (online) 1872-9096
    ISSN 0166-3542
    DOI 10.1016/j.antiviral.2006.02.010
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  7. Article ; Online: Synthesis and Antiviral Evaluation of Octadecyloxyethyl Benzyl 9-[(2-Phosphonomethoxy)ethyl]guanine (ODE-Bn-PMEG), a Potent Inhibitor of Transient HPV DNA Amplification.

    Beadle, James R / Valiaeva, Nadejda / Yang, Guang / Yu, Jei-Hwa / Broker, Thomas R / Aldern, Kathy A / Harden, Emma A / Keith, Kathy A / Prichard, Mark N / Hartman, Tracy / Buckheit, Robert W / Chow, Louise T / Hostetler, Karl Y

    Journal of medicinal chemistry

    2016  Volume 59, Issue 23, Page(s) 10470–10478

    Abstract: Human papillomavirus (HPV) high-risk genotypes such as HPV-16 and HPV-18 cause the majority of anogenital tract carcinomas, including cervical cancer, the second most common malignancy in women worldwide. Currently there are no approved antiviral agents ... ...

    Abstract Human papillomavirus (HPV) high-risk genotypes such as HPV-16 and HPV-18 cause the majority of anogenital tract carcinomas, including cervical cancer, the second most common malignancy in women worldwide. Currently there are no approved antiviral agents that reduce or eliminate HPV and reverse virus-associated pathology. We synthesized and evaluated several alkoxyalkyl acyclic nucleoside phosphonate diesters and identified octadecyloxyethyl benzyl 9-[(2-phosphonomethoxy)ethyl]guanine (ODE-Bn-PMEG) as an active compound which strongly inhibited transient amplification of HPV-11, -16, and -18 origin-containing plasmid DNA in transfected cells at concentrations well below its cytotoxic concentrations. ODE-Bn-PMEG demonstrated increased uptake in human foreskin fibroblast cells and was readily converted in vitro to the active antiviral metabolite, PMEG diphosphate. The P-chiral enantiomers of ODE-Bn-PMEG were obtained and appeared to have equivalent antiviral activities against HPV. ODE-Bn-PMEG is a promising candidate for the local treatment of HPV-16 and HPV-18 and other high-risk types, an important unmet medical need.
    MeSH term(s) Antiviral Agents/chemical synthesis ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Cell Line, Tumor ; DNA, Viral/drug effects ; Dose-Response Relationship, Drug ; Guanine/analogs & derivatives ; Guanine/chemical synthesis ; Guanine/chemistry ; Guanine/pharmacology ; HEK293 Cells ; HIV/drug effects ; Herpesvirus 2, Human/drug effects ; Humans ; Leukocytes, Mononuclear/drug effects ; Leukocytes, Mononuclear/virology ; Molecular Structure ; Nucleic Acid Amplification Techniques ; Organophosphonates/chemical synthesis ; Organophosphonates/chemistry ; Organophosphonates/pharmacology ; Papillomaviridae/drug effects ; Papillomaviridae/genetics ; Structure-Activity Relationship ; Virus Replication/drug effects
    Chemical Substances Antiviral Agents ; DNA, Viral ; Organophosphonates ; octadecyloxyethyl 9-(2-(phosphonomethoxy)ethyl)guanine ; Guanine (5Z93L87A1R)
    Language English
    Publishing date 2016-11-28
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.6b00659
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  8. Article: Activity and mechanism of action of N-methanocarbathymidine against herpesvirus and orthopoxvirus infections.

    Prichard, Mark N / Keith, Kathy A / Quenelle, Debra C / Kern, Earl R

    Antimicrobial agents and chemotherapy

    2005  Volume 50, Issue 4, Page(s) 1336–1341

    Abstract: N-Methanocarbathymidine [(N)-MCT] is a conformationally locked nucleoside analog that is active against some herpesviruses and orthopoxviruses in vitro. The antiviral activity of this molecule is dependent on the type I thymidine kinase (TK) in herpes ... ...

    Abstract N-Methanocarbathymidine [(N)-MCT] is a conformationally locked nucleoside analog that is active against some herpesviruses and orthopoxviruses in vitro. The antiviral activity of this molecule is dependent on the type I thymidine kinase (TK) in herpes simplex virus and also appears to be dependent on the type II TK expressed by cowpox and vaccinia viruses, suggesting that it is a substrate for both of these divergent forms of the enzyme. The drug is also a good inhibitor of viral DNA synthesis in both viruses and is consistent with inhibition of the viral DNA polymerase once it is activated by the viral TK homologs. This mechanism of action explains the rather unusual spectrum of activity, which is limited to orthopoxviruses, alphaherpesviruses, and Epstein-Barr virus, since these viruses express molecules with TK activity that can phosphorylate and thus activate the drug. The compound is also effective in vivo and reduces the mortality of mice infected with orthopoxviruses, as well as those infected with herpes simplex virus type 1 when treatment is initiated 24 h after infection. These results indicate that (N)-MCT is active in vitro and in vivo, and its mechanism of action suggests that the molecule may be an effective therapeutic for orthopoxvirus and herpesvirus infections, thus warranting further development.
    MeSH term(s) Animals ; Antiviral Agents/therapeutic use ; Cells, Cultured ; DNA, Viral/biosynthesis ; Female ; Herpesviridae Infections/drug therapy ; Humans ; Mice ; Mice, Inbred BALB C ; Phosphorylation ; Poxviridae Infections/drug therapy ; Thymidine/analogs & derivatives ; Thymidine/pharmacology ; Thymidine/therapeutic use ; Thymidine Kinase/metabolism
    Chemical Substances Antiviral Agents ; DNA, Viral ; Thymidine Kinase (EC 2.7.1.21) ; (north)-methanocarbathymidine (LTM5S02010) ; Thymidine (VC2W18DGKR)
    Language English
    Publishing date 2005-12-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 217602-6
    ISSN 1098-6596 ; 0066-4804
    ISSN (online) 1098-6596
    ISSN 0066-4804
    DOI 10.1128/AAC.50.4.1336-1341.2006
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  9. Article ; Online: Identification of protein-protein interaction inhibitors targeting vaccinia virus processivity factor for development of antiviral agents.

    Schormann, Norbert / Sommers, Charnell Inglis / Prichard, Mark N / Keith, Kathy A / Noah, James W / Nuth, Manunya / Ricciardi, Robert P / Chattopadhyay, Debasish

    Antimicrobial agents and chemotherapy

    2011  Volume 55, Issue 11, Page(s) 5054–5062

    Abstract: Poxvirus uracil DNA glycosylase D4 in association with A20 and the catalytic subunit of DNA polymerase forms the processive polymerase complex. The binding of D4 and A20 is essential for processive polymerase activity. Using an AlphaScreen assay, we ... ...

    Abstract Poxvirus uracil DNA glycosylase D4 in association with A20 and the catalytic subunit of DNA polymerase forms the processive polymerase complex. The binding of D4 and A20 is essential for processive polymerase activity. Using an AlphaScreen assay, we identified compounds that inhibit protein-protein interactions between D4 and A20. Effective interaction inhibitors exhibited both antiviral activity and binding to D4. These results suggest that novel antiviral agents that target the protein-protein interactions between D4 and A20 can be developed for the treatment of infections with poxviruses, including smallpox.
    MeSH term(s) Antiviral Agents/pharmacology ; Cell Line ; DNA Glycosylases/metabolism ; Humans ; Protein Binding ; Vaccinia virus/drug effects ; Viral Proteins/metabolism
    Chemical Substances Antiviral Agents ; Viral Proteins ; DNA Glycosylases (EC 3.2.2.-)
    Language English
    Publishing date 2011-08-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 217602-6
    ISSN 1098-6596 ; 0066-4804
    ISSN (online) 1098-6596
    ISSN 0066-4804
    DOI 10.1128/AAC.00278-11
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  10. Article ; Online: Synthesis, metabolic stability and antiviral evaluation of various alkoxyalkyl esters of cidofovir and 9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine.

    Ruiz, Jacqueline / Beadle, James R / Buller, R Mark / Schreiwer, Jill / Prichard, Mark N / Keith, Kathy A / Lewis, Kenneth C / Hostetler, Karl Y

    Bioorganic & medicinal chemistry

    2011  Volume 19, Issue 9, Page(s) 2950–2958

    Abstract: Alkoxyalkyl esters of cidofovir (CDV) are orally active agents which inhibit the replication of a variety of double stranded DNA (dsDNA) viruses including variola, vaccinia, ectromelia, herpes simplex virus, cytomegalovirus, adenovirus and others. One of ...

    Abstract Alkoxyalkyl esters of cidofovir (CDV) are orally active agents which inhibit the replication of a variety of double stranded DNA (dsDNA) viruses including variola, vaccinia, ectromelia, herpes simplex virus, cytomegalovirus, adenovirus and others. One of these compounds, hexadecyloxypropyl-CDV (HDP-CDV, CMX001) is in clinical development for prevention and treatment of poxvirus infection, vaccination complications, and for infections caused by cytomegalovirus, adenovirus, herpesviruses and other dsDNA viruses. This class of lipid analogs is potentially prone to undergo omega oxidation of the alkyl moiety which can lead to a short chain carboxylic acid lacking antiviral activity. To address this issue, we synthesized a series of alkoxyalkyl or alkyl glycerol esters of CDV and (S)-HPMPA having modifications in the structure of the alkyl residue. Antiviral activity was assessed in cells infected with vaccinia, cowpox or ectromelia viruses. Metabolic stability was determined in S9 membrane fractions from rat, guinea pig, monkey and human liver. All compounds had substantial antiviral activity in cells infected with vaccinia, cowpox or ectromelia. Metabolic stability was lowest in monkey liver S9 incubations where rapid disappearance of HDP-CDV and HDP-(S)-HPMPA was noted. Metabolic stability in monkey preparations increased substantially when a ω-1 methyl group (15-methyl-HDP-CDV) or a terminal cyclopropyl residue (14-cyclopropyl-tetradecyloxypropyl-CDV) was present in the alkyl chain. The most stable compound was 1-O-octadecyl-2-O-benzyl-sn-glycero-3-CDV (ODBG-CDV) which was not metabolized extensively by monkey liver S9. In rat, guinea pig or human liver S9 incubations, most of the modified antiviral compounds were considerably more stable.
    MeSH term(s) Adenine/analogs & derivatives ; Adenine/chemical synthesis ; Adenine/chemistry ; Adenine/pharmacology ; Animals ; Antiviral Agents/chemical synthesis ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Cidofovir ; Cowpox virus/drug effects ; Cytosine/analogs & derivatives ; Cytosine/chemical synthesis ; Cytosine/chemistry ; Cytosine/pharmacology ; Ectromelia virus/drug effects ; Esters ; Guinea Pigs ; Haplorhini ; Humans ; Liver/metabolism ; Organophosphonates/chemical synthesis ; Organophosphonates/chemistry ; Organophosphonates/pharmacology ; Rats ; Vaccinia virus/drug effects
    Chemical Substances Antiviral Agents ; Esters ; Organophosphonates ; Cytosine (8J337D1HZY) ; 9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine (CJC8PO1KQ3) ; Adenine (JAC85A2161) ; Cidofovir (JIL713Q00N)
    Language English
    Publishing date 2011-03-23
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1161284-8
    ISSN 1464-3391 ; 0968-0896
    ISSN (online) 1464-3391
    ISSN 0968-0896
    DOI 10.1016/j.bmc.2011.03.034
    Database MEDical Literature Analysis and Retrieval System OnLINE

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