scholarly journals (Z)- and (E)-2-(Hydroxymethylcyclopropylidene)-Methylpurines and Pyrimidines as Antiviral Agents

1998 ◽  
Vol 9 (4) ◽  
pp. 57-68 ◽  
Author(s):  
Y-L Qiu ◽  
RG Ptak ◽  
JM Breitenbach ◽  
J-S Lin ◽  
Y-C Cheng ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Antiviral Agents ◽  
Human Herpesvirus ◽  
Murine Cytomegalovirus ◽  
Strong Inhibitor ◽  
Varicella Zoster ◽  
Daudi Cells ◽  
Hiv 1 ◽  
Hsv 1

Several Z- and E-methylenecyclopropane nucleoside analogues were synthesized and evaluated for antiviral activity. Reaction of the Z- and E-2-amino-6-chloropurine methylenecyclopropanes with ammonia or cyclopropylamine gave 2,6-diamino or 2-amino-6-cyclopropylamino analogues. Alkylation elimination of N4-acetylcytosine with ethyl Z- and E-2-bromo-2-bromomethylcyclopropane-1-carboxylates gave a mixture of the Z-and E-methylenecyclopropane derivatives of cytosine. Reduction furnished a mixture of syncytol and the E isomer. Benzoylation led to the respective N4-benzoyl derivatives which were separated by chromatography. Debenzoylation afforded pure syncytol and the E isomer. Alkylation of 2,4-bis-O-trimethylsilylthymine with ethyl Z- and E-2-bromo-2-bromomethylcyclopropane-1-carboxylates gave the corresponding Z- and E-1-bromo-cyclopropylmethylderivatives of thymine. Base-catalysed elimination of HBr gave Z- and E-methylenecyclopropane carboxylic esters. Reduction furnished, after chromatographic separation, synthymol and the E isomer. The Z/E isomeric assignment of the obtained products followed from 1H NMR spectroscopy. The methylenecyclopropane analogues were tested for antiviral activity in vitro against human and murine cytomegalovirus (HCMV, MCMV), Epstein–Barr virus (EBV), varicella zoster virus (VZV), hepatitis B virus (HBV), herpes simplex virus types 1 and 2 (HSV-1, HSV-2), human herpesvirus 6 (HHV-6) and human immunodeficiency virus type 1 (HIV-1). The Z-2-amino-6-cyclopropylaminopurine analogue was the most effective agent against HCMV (EC50 or EC90 0.4–2 μM) followed by syncytol and the Z-2,6-diaminopurine analogues (EC50 or EC90 3.4–29 and 11–24 μM, respectively). The latter compound was also a strong inhibitor of MCMV (EC50 0.6 μM). Syncytol was the most potent against EBV (EC50 <0.41 and 2.5 μM) followed by the Z-2,6-diaminopurine (EC50 1.5 and 6.9 μM) and the Z-2-amino-6-cyclopropylaminopurine derivative (EC50 11.8 μM). Syncytol was also most effective against VZV (EC50 3.6 μM). Activity against HSV-1, HSV-2 and HHV-6 was generally lower; synthymol had an EC50 of 2 μM against HSV-1 (ELISA) and 1.3 μM against EBV in Daudi cells but was inactive in other assays. The 2-amino-6-cyclopropylamino analogue displayed EC50 values between 215 and >74 μM in HSV-1 and HSV-2 assays. 2-Amino-6-cyclopropylaminopurine and 2,6-diaminopurine derivatives were effective against HBV (EC50 2 and 10 μM, respectively), whereas none of the analogues inhibited HIV-1 at a higher virus load. Syncytol and the E isomer were equipotent against EBV in Daudi cells but the E isomer was much less effective in DNA hybridization assays. The E-2,6-diaminopurine analogue and E isomer of synthymol were devoid of antiviral activity.

scholarly journals In Vitro Activity and Mechanism of Action of Methylenecyclopropane Analogs of Nucleosides against Herpesvirus Replication

2005 ◽  
Vol 49 (3) ◽  
pp. 1039-1045 ◽  
Author(s):  
Earl R. Kern ◽  
Nicole L. Kushner ◽  
Caroll B. Hartline ◽  
Stephanie L. Williams-Aziz ◽  
Emma A. Harden ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Human Herpesvirus ◽  
Murine Cytomegalovirus ◽  
Enzyme Linked Immunosorbent Assay ◽  
Herpesvirus Type ◽  
Varicella Zoster ◽  
Barr Virus ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT We have reported previously that methylenecyclopropane analogs of nucleosides have excellent activity against certain members of the herpesvirus family. A second generation, the 2,2-bis-hydroxymethyl derivatives, were synthesized, and 18 compounds were tested for activity in vitro against herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), human and murine cytomegalovirus (HCMV and MCMV), varicella-zoster virus (VZV), and Epstein-Barr virus (EBV). Selected analogs were also evaluated against human herpesvirus type 6 (HHV-6) and HHV-8. None of the 18 compounds had activity against HSV-1 or HSV-2, but four were active against VZV by plaque reduction (PR) assay at 50% effective concentration (EC50) levels of ≤50 μM. Six of the 18 compounds were active against HCMV by cytopathic effect or PR assays with EC50s of 0.5 to 44 μM, and all were active against MCMV by PR (0.3 to 54 μM). Four of the compounds were active against EBV by enzyme-linked immunosorbent assay (<0.3 to 4.4 μM). Four compounds with CMV activity were also active against HHV-6A and HHV-6B (0.7 to 28 μM), and three compounds were active against HHV-8 (5.5 to 16 μM). One of these, ZSM-I-62, had particularly good activity against CMV, HHV-6, and HHV-8, with EC50s of 0.7 to 8 μM. Toxicity was evaluated in adherent and nonadherent cells, and minimal cytotoxicity was observed. Mechanism of action studies with HCMV suggested that these compounds are phosphorylated by the ppUL97 phosphotransferase and are potent inhibitors of viral DNA synthesis. These results indicate that at least one of these compounds may have potential for use in treating CMV and other herpesvirus infections in humans.

scholarly journals Amphipathic DNA Polymers Exhibit Antiherpetic Activity In Vitro and In Vivo

2008 ◽  
Vol 52 (8) ◽  
pp. 2727-2733 ◽  
Author(s):  
David I. Bernstein ◽  
Nathalie Goyette ◽  
Rhonda Cardin ◽  
Earl R. Kern ◽  
Guy Boivin ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Broad Spectrum ◽  
Parent Compound ◽  
Human Herpesvirus ◽  
Varicella Zoster ◽  
Barr Virus ◽  
Simplex Virus ◽  
Acid Stable

ABSTRACT Phosphorothioated oligonucleotides have a sequence-independent antiviral activity as amphipathic polymers (APs). The activity of these agents against herpesvirus infections in vitro and in vivo was investigated. The previously established sequence-independent, phosphorothioation-dependent antiviral activity of APs was confirmed in vitro by showing that a variety of equivalently sized homo- and heteropolymeric AP sequences were similarly active against herpes simplex virus type 1 (HSV-1) infection in vitro compared to the 40mer degenerate parent compound (REP 9), while the absence of phosphorothioation resulted in the loss of antiviral activity. In addition, REP 9 demonstrated in vitro activity against a broad spectrum of other herpesviruses: HSV-2 (50% effective concentration [EC50], 0.02 to 0.06 μM), human cytomegalovirus (EC50, 0.02 to 0.13 μM), varicella zoster virus (EC50, <0.02 μM), Epstein-Barr virus (EC50, 14.7 μM) and human herpesvirus types 6A/B (EC50, 2.9 to 10.2 μM). The murine microbicide model of genital HSV-2 was then used to evaluate in vivo activity. REP 9 (275 mg/ml) protected 75% of animals from disease and infection when provided 5 or 30 min prior to vaginal challenge. When an acid-stable analog (REP 9C) was used, 75% of mice were protected when treated with 240 mg/ml 5 min prior to infection (P < 0.001), while a lower dose (100 mg/ml) protected 100% of the mice (P < 0.001). The acid stable REP 9C formulation also provided protection at 30 min (83%, P < 0.001) and 60 min (50%, P = 0.07) against disease. These observations suggest that APs may have microbicidal activity and potential as broad-spectrum antiherpetic agents and represent a novel class of agents that should be studied further.

Lipid prodrugs of phosphonoacids: greatly enhanced antiviral activity of 1-O-octadecyl-sn-glycero-3-phosphonoformate in HIV-1, HSV-1 and HCMV-infected cells, in vitro

1996 ◽  
Vol 31 (1-2) ◽  
pp. 59-67 ◽  
Author(s):  
Karl Y. Hostetler ◽  
Ganesh D. Kini ◽  
James R. Beadle ◽  
Kathy A. Aldern ◽  
Michael F. Gardner ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Infected Cells ◽  
Hiv 1 ◽  
Hsv 1

Polysulfonates Derived from Metal Thiolate Complexes as Inhibitors of HIV-1 and Various other Enveloped Viruses In Vitro

2002 ◽  
Vol 13 (3) ◽  
pp. 185-195 ◽  
Author(s):  
Donald E Bergstrom ◽  
Xiaoping Lin ◽  
Troy D Wood ◽  
Myriam Witvrouw ◽  
Satoru Ikeda ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Palladium Complex ◽  
Platinum Complex ◽  
Cadmium Complex ◽  
Junin Virus ◽  
Tacaribe Virus ◽  
Junín Virus ◽  
Hiv 1 ◽  
Hsv 1

Sodium 2-mercaptoethanesulfonate reacts with the metal ions Pd(II), Pt(II), Ag(I), Cd(II) and Zn(II) to yield complexes containing multiple anionic sulfonate sites. On the basis of spectroscopic and other analytical data the complexes were assigned the tentative molecular formulas: Pd6(SCH2CH2SO3Na)12, Ptn(SCH2CH2SO3Na)2n+2, Agn(SCH2CH2SO3Na)n, Na2Zn4(SCH2CH2SO3Na)10, and Na2Cd4(SCH2CH2SO3Na)10. The complexes displayed a variety of differences in activity towards DNA and RNA viruses. The platinum complex showed no measurable cytotoxicity and exhibited a spectrum of antiviral activity resembling that of dextran sulfate. It was active against HIV-1 and HIV-2, herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), thymidine kinase-deficient HSV-1, human cytomegalovirus, vesicular stomatitis virus (VSV), influenza A virus, respiratory syncytial virus (RSV), Sindbis virus, Junin virus and Tacaribe virus. The palladium complex also showed no measurable cytotoxicity, but was completely inactive against most viruses, with one notable exception: both HIV-1 and HIV-2 were substantially inhibited by the palladium complex. The silver complex showed significantly less antiviral activity and greater cytotoxicity than the platinum complex but did show some selectivity against RSV. The zinc complex showed only modest activity against VSV, RSV, Junin virus, and Tacaribe virus, and like the silver compound was more cytotoxic than either the platinum or palladium complex. The cadmium complex was toxic to all of the cell lines used for in vitro evaluation of antiviral activity. Based on these results, the platinum and palladium compounds appear to be promising candidates for further studies, that is, as vaginal microbicides in the prevention of genital HIV and/or HSV transmission.

scholarly journals Evaluation of Antiviral Activities of Curcumin Derivatives against HSV-1 in Vero Cell Line

2010 ◽  
Vol 5 (12) ◽  
pp. 1934578X1000501 ◽  
Author(s):  
Keivan Zandi ◽  
Elissa Ramedani ◽  
Khosro Mohammadi ◽  
Saeed Tajbakhsh ◽  
Iman Deilami ◽  
...  
Keyword(s):  
Cell Culture ◽  
Antiviral Activity ◽  
Vero Cell ◽  
Cell Line ◽  
Antiviral Agents ◽  
Antiviral Drug ◽  
In Vitro Study ◽  
Vero Cell Line ◽  
Hsv 1

Antiviral drug resistance is one of the most common problems in medicine, and, therefore, finding new antiviral agents, especially from natural resources, seems to be necessary. This study was designed to assay the antiviral activity of curcumin and its new derivatives like gallium-curcumin and Cu-curcumin on replication of HSV-1 in cell culture. The research was performed as an in vitro study in which the antiviral activity of different concentrations of three substances including curcumin, Gallium-curcumin and Cu-curcumin were tested on HSV-1. The cytotoxicity of the tested compounds was also evaluated on the Vero cell line. The CC50 values for curcumin, gallium-curcumin and Cu-curcumin were 484.2 μg/mL, 255.8 μg/mL and 326.6 μg/mL, respectively, and the respective IC50 values 33.0 μg/mL, 13.9 μg/mL and 23.1 μg/mL. The calculated SI values were 14.6, 18.4 and 14.1, respectively. The results showed that curcumin and its new derivatives have remarkable antiviral effects on HSV-1 in cell culture.

scholarly journals Inhibition of Herpesvirus Replication by 5-Substituted 4′-Thiopyrimidine Nucleosides

2009 ◽  
Vol 53 (12) ◽  
pp. 5251-5258 ◽  
Author(s):  
Mark N. Prichard ◽  
Debra C. Quenelle ◽  
Caroll B. Hartline ◽  
Emma A. Harden ◽  
Geraldine Jefferson ◽  
...  
Keyword(s):  
Human Herpesvirus ◽  
Good Activity ◽  
Varicella Zoster ◽  
Barr Virus ◽  
Resistant Strains ◽  
Epstein Barr ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT A series of 4′-thionucleosides were synthesized and evaluated for activities against orthopoxviruses and herpesviruses. We reported previously that one analog, 5-iodo-4′-thio-2′-deoxyuridine (4′-thioIDU), exhibits good activity both in vitro and in vivo against two orthopoxviruses. This compound also has good activity in cell culture against many of the herpesviruses. It inhibited the replication of herpes simplex virus type 1 (HSV-1), HSV-2, and varicella-zoster virus with 50% effective concentrations (EC50s) of 0.1, 0.5, and 2 μM, respectively. It also inhibited the replication of human cytomegalovirus (HCMV) with an EC50 of 5.9 μM but did not selectively inhibit Epstein-Barr virus, human herpesvirus 6, or human herpesvirus 8. While acyclovir-resistant strains of HSV-1 and HSV-2 were comparatively resistant to 4′-thioIDU, it retained modest activity (EC50s of 4 to 12 μM) against these strains. Some ganciclovir-resistant strains of HCMV also exhibited reduced susceptibilities to the compound, which appeared to be related to the specific mutations in the DNA polymerase, consistent with the observed incorporation of the compound into viral DNA. The activity of 4′-thioIDU was also evaluated using mice infected intranasally with the MS strain of HSV-2. Although there was no decrease in final mortality rates, the mean length of survival after inoculation increased significantly (P < 0.05) for all animals receiving 4′-thioIDU. The findings from the studies presented here suggest that 4′-thioIDU is a good inhibitor of some herpesviruses, as well as orthopoxviruses, and this class of compounds warrants further study as a therapy for infections with these viruses.

scholarly journals The Varicella-Zoster Virus Portal Protein Is Essential for Cleavage and Packaging of Viral DNA

2014 ◽  
Vol 88 (14) ◽  
pp. 7973-7986 ◽  
Author(s):  
Melissa A. Visalli ◽  
Brittany L. House ◽  
Anca Selariu ◽  
Hua Zhu ◽  
Robert J. Visalli
Keyword(s):  
Varicella Zoster Virus ◽  
Deletion Mutant ◽  
Human Herpesvirus ◽  
Artificial Chromosome ◽  
Cell Nuclei ◽  
Viral Dna ◽  
Portal Protein ◽  
Varicella Zoster ◽  
Hsv 1

ABSTRACTThe varicella-zoster virus (VZV) open reading frame 54 (ORF54) gene encodes an 87-kDa monomer that oligomerizes to form the VZV portal protein, pORF54. pORF54 was hypothesized to perform a function similar to that of a previously described herpes simplex virus 1 (HSV-1) homolog, pUL6. pUL6 and the associated viral terminase are required for processing of concatemeric viral DNA and packaging of individual viral genomes into preformed capsids. In this report, we describe two VZV bacterial artificial chromosome (BAC) constructs with ORF54 gene deletions, Δ54L (full ORF deletion) and Δ54S (partial internal deletion). The full deletion of ORF54 likely disrupted essential adjacent genes (ORF53 and ORF55) and therefore could not be complemented on an ORF54-expressing cell line (ARPE54). In contrast, Δ54S was successfully propagated in ARPE54 cells but failed to replicate in parental, noncomplementing ARPE19 cells. Transmission electron microscopy confirmed the presence of only empty VZV capsids in Δ54S-infected ARPE19 cell nuclei. Similar to the HSV-1 genome, the VZV genome is composed of a unique long region (UL) and a unique short region (US) flanked by inverted repeats. DNA from cells infected with parental VZV (VZVLUCstrain) contained the predicted ULand UStermini, whereas cells infected with Δ54S contained neither. This result demonstrates that Δ54S is not able to process and package viral DNA, thus making pORF54 an excellent chemotherapeutic target. In addition, the utility of BAC constructs Δ54L and Δ54S as tools for the isolation of site-directed ORF54 mutants was demonstrated by recombineering single-nucleotide changes within ORF54 that conferred resistance to VZV-specific portal protein inhibitors.IMPORTANCEAntivirals with novel mechanisms of action would provide additional therapeutic options to treat human herpesvirus infections. Proteins involved in the herpesviral DNA encapsidation process have become promising antiviral targets. Previously, we described a series ofN-α-methylbenzyl-N′-aryl thiourea analogs that target the VZV portal protein (pORF54) and prevent viral replicationin vitro. To better understand the mechanism of action of these compounds, it is important to define the structural and functional characteristics of the VZV portal protein. In contrast to HSV, no VZV mutants have been described for any of the seven essential DNA encapsidation genes. The VZV ORF54 deletion mutant described in this study represents the first VZV encapsidation mutant reported to date. We demonstrate that the deletion mutant can serve as a platform for the isolation of portal mutants via recombineering and provide a strategy for more in-depth studies of VZV portal structure and function.

scholarly journals Antiherpesvirus Activities of Two Novel 4′-Thiothymidine Derivatives, KAY-2-41 and KAH-39-149, Are Dependent on Viral and Cellular Thymidine Kinases

2014 ◽  
Vol 58 (8) ◽  
pp. 4328-4340 ◽  
Author(s):  
Natacha Coen ◽  
Sophie Duraffour ◽  
Kazuhiro Haraguchi ◽  
Jan Balzarini ◽  
Joost J. van den Oord ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Antiviral Activity ◽  
Epstein Barr Virus ◽  
Varicella Zoster ◽  
Barr Virus ◽  
Epstein Barr ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTThe emergence of drug-resistant herpesviruses represents a significant problem in clinical practice, primarily in immunocompromised patients. Furthermore, effective antiviral therapies against gammaherpesvirus-associated diseases are lacking. Here, we present two thiothymidine derivatives, KAY-2-41 and KAH-39-149, with different spectra of antiviral activity from those of the reference antiherpetic drugs, showing inhibitory activities against herpes simplex virus, varicella-zoster virus (VZV), and particularly against Epstein-Barr virus, with high selectivityin vitro. While KAY-2-41- and KAH-39-149-resistant herpesviruses were found to harbor mutations in the viral thymidine kinase (TK), these mutations conferred only low levels of resistance to these drugs but high levels to other TK-dependent drugs. Also, antiviral assays in HeLa TK-deficient cells showed a lack of KAY-2-41 and KAH-39-149 activities against herpes simplex virus 1 (HSV-1) and HSV-2 TK-deficient mutants. Furthermore, enzymatic TK assays showed the ability of HSV-1 TK, VZV TK, and cellular TK1 and TK2 to recognize and phosphorylate KAY-2-41 and KAH-39-149. These results demonstrate that the compounds depend on both viral and host TKs to exert antiviral activity. Additionally, the antiviral efficacy of KAH-39-149 proved to be superior to that of KAY-2-41 in a mouse model of gammaherpesvirus infection, highlighting the potential of this class of antiviral agents for further development as selective therapeutics against Epstein-Barr virus.

scholarly journals Comparative Activities of Lipid Esters of Cidofovir and Cyclic Cidofovir against Replication of Herpesviruses In Vitro

2005 ◽  
Vol 49 (9) ◽  
pp. 3724-3733 ◽  
Author(s):  
Stephanie L. Williams-Aziz ◽  
Caroll B. Hartline ◽  
Emma A. Harden ◽  
Shannon L. Daily ◽  
Mark N. Prichard ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Human Herpesvirus ◽  
Murine Cytomegalovirus ◽  
In Vitro Assays ◽  
Varicella Zoster ◽  
Barr Virus ◽  
Lipid Ester ◽  
Epstein Barr ◽  
Simplex Virus

ABSTRACT Cidofovir (CDV) is an effective therapy for certain human cytomegalovirus (HCMV) infections in immunocompromised patients that are resistant to other antiviral drugs, but the compound is not active orally. To improve oral bioavailability, a series of lipid analogs of CDV and cyclic CDV (cCDV), including hexadecyloxypropyl-CDV and -cCDV and octadecyloxyethyl-CDV and -cCDV, were synthesized and found to have multiple-log-unit enhanced activity against HCMV in vitro. On the basis of the activity observed with these analogs, additional lipid esters were synthesized and evaluated for their activity against herpes simplex virus (HSV) types 1 and 2, human cytomegalovirus, murine cytomegalovirus, varicella-zoster virus (VZV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), and HHV-8. Using several different in vitro assays, concentrations of drug as low as 0.001 μM reduced herpesvirus replication by 50% (EC50) with the CDV analogs, whereas the cCDV compounds were generally less active. In most of the assays performed, the EC50 values of the lipid esters were at least 100-fold lower than the EC50 values for unmodified CDV or cCDV. The lipid analogs were also active against isolates that were resistant to CDV, ganciclovir, or foscarnet. These results indicate that the lipid ester analogs are considerably more active than CDV itself against HSV, VZV, CMV, EBV, HHV-6, and HHV-8 in vitro, suggesting that they may have potential for the treatment of infections caused by a variety of herpesviruses.

Phosphoramidate derivatives of acyclovir: Synthesis and antiviral activity in HIV-1 and HSV-1 models in vitro

2012 ◽  
Vol 20 (19) ◽  
pp. 5802-5809 ◽  
Author(s):  
Natalia F. Zakirova ◽  
Alexander V. Shipitsyn ◽  
Maxim V. Jasko ◽  
Maria M. Prokofjeva ◽  
Valeria L. Andronova ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Derivatives Of ◽  
Hiv 1 ◽  
Hsv 1
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