Towards an Effective Chemotherapy of Virus Infections: Therapeutic Potential of Cidofovir [(S)-1-[3-Hydroxy-2-(phosphonomethoxy)propyl]cytosine, HPMPC] for the Treatment of DNA Virus Infections

1998 ◽  
Vol 63 (4) ◽  
pp. 480-506 ◽  
Author(s):  
Erik De Clercq
Keyword(s):  
Antiviral Activity ◽  
Therapeutic Potential ◽  
Antiviral Agents ◽  
Human Herpesvirus ◽  
Antiviral Agent ◽  
Molluscum Contagiosum ◽  
Virus Infections ◽  
Laryngeal Papillomatosis ◽  
Dna Virus ◽  
Herpesvirus Type

The acyclic nucleoside phosphonate HPMPC [(S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine, cidofovir, Vistide®] has a unique profile among the antiviral agents in that it is active against a much broader spectrum of DNA viruses than any other antiviral agent, and, furthermore, shows a long-lasting antiviral activity, thus enabling infrequent dosing (for intravenous administration, as infrequent as once a week or every other week). HPMPC owes its antiviral activity to a selective inhibitory effect on viral DNA synthesis: as has been demonstrated for human cytomegalovirus (CMV), HPMPC leads to DNA chain termination following the incorporation of two consecutive HPMPC residues. The activity spectrum of HPMPC encompasses herpes-, adeno-, polyoma-, papilloma-, and poxviruses. It has been approved for the treatment of CMV retinitis in AIDS patients and has proved effective in the treatment of herpes simplex virus (HSV) infections (particularly those that are resistant to acyclovir), human papilloma virus (HPV) infections (e.g. anogenital warts and recurrent laryngeal papillomatosis) and poxvirus infections (e.g. molluscum contagiosum). It is now further explored for its therapeutic potential in the treatment of HSV, CMV and HPV infections, and various other DNA virus infections, including adenovirus infections (e.g. keratoconjunctivitis), polyomavirus infections such as PML (progressive multifocal leukoencephalopathy), poxvirus infections (e.g. molluscum contagiosum), Epstein-Barr virus (EBV)-associated infections, and human herpesvirus type 8 (HHV-8)-associated infections (e.g. Kaposi's sarcoma).

scholarly journals Mechanism of the Antiviral Activity of New Aurintricarboxylic Acid Analogues

1996 ◽  
Vol 7 (3) ◽  
pp. 142-152 ◽  
Author(s):  
D. Reymen ◽  
M. Witvrouw ◽  
J. A. Esté ◽  
J. Neyts ◽  
D. Schols ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Parent Compound ◽  
Flow Cytometric Analysis ◽  
Human Herpesvirus ◽  
Enveloped Viruses ◽  
Herpesvirus Type ◽  
Aurintricarboxylic Acid ◽  
Dna And Rna ◽  
Human Herpesvirus Type ◽  
Hiv 1

Various new aurintricarboxylic acid (ATA) polymer analogues have been evaluated for their antiviral activity against a wide array of DNA and RNA viruses, and their mechanism of action against human cytomegalovirus (HCMV) and human immunodeficiency virus type 1 (HIV-1). Most of the polymers exhibited marked antiviral activity against a variety of enveloped viruses, but not against non-enveloped viruses. The ATA polymers displayed the most pronounced activity against HIV-1, HCMV and human herpesvirus type 6 (HHV-6). Their action against HCMV and HIV could be ascribed to inhibition of the initial attachment of virus particles to the cells. Using radiolabelled virus, we proved that the polymers inhibit the binding of HCMV to HEL fibroblasts. By flow cytometric analysis, we demonstrated that these new polymers interfere with (i) the binding of OKT4A monoclonal antibody (mAb) to the cellular CD4 receptor, (ii) the binding of anti-gp120 mAb to HIV-1 glycoprotein (gp) 120, and (iii) the adsorption of HIV-1 virions and recombinant HIV-1gp120 (rgp120) to MT-4 cells. The presence of a salicylic acid substituent on the central bridging carbon in the parent compound ATA seems to play an important role in the anti-HIV activity of these ATA related polymer analogues.

scholarly journals Features of change of immune status indicators in individuals with active and latent forms of herpes-virus infections

2021 ◽  
Vol 38 (1) ◽  
pp. 46-63
Author(s):  
T. V. Solomay ◽  
T. A. Semenenko ◽  
N. V. Karazhas ◽  
T. N. Rybalkina ◽  
P. A. Veselovsky ◽  
...  
Keyword(s):  
Immune Status ◽  
Clinical Manifestations ◽  
Human Herpesvirus ◽  
Virus Infections ◽  
Herpes Simplex Viruses ◽  
Herpesvirus Type ◽  
Blood Tests ◽  
Epstein Barr ◽  
Prospective Longitudinal ◽  
Hsv 1

Objective. The aim of the study is to investigate the peculiarities of changes in the immune status of individuals with active and latent forms of herpesvirus infections. Herpesvirus infections are an urgent problem of modern health care. Materials and methods. The prospective longitudinal cohort study included 92 permanent blood donors who were examined twice at 6-month intervals for the presence of specific IgM and IgG antibodies and antigens of herpes simplex viruses 1, 2, Epstein-Barr, cytomegalovirus, human herpesvirus type 6, as well as humoral immunity indicators. Results. In the period from October to April, 68.5 % of blood and its components donors were found to have markers of active herpesvirus infection caused by HSV 1, 2, EBV, CMV, and HHV6. The combination of the detected markers in the absence of clinical manifestations and changes in General and biochemical blood tests indicated asymptomatic reactivation of latent infection. The frequency of reactivations in the autumn and spring months is the same. The absence of IgG production after asymptomatic reactivation of HSV-2 and HHV-6 infections and an increase in IgG concentrations to HSV-1, EBV, and CMV were revealed. EBV infection is the most common among the studied nosologies (98.91 %) and is characterized by statistically significantly higher levels of specific IgG. The effect of asymptomatic reactivation of herpesvirus infections on the levels of total IDA, IgM, IgG, IDE, and CEC was not established. Conclusions. Asymptomatic reactivation of herpesvirus infections does not significantly affect the changes in immune status indicators, and the absence of clinical manifestations, and significant changes in General and biochemical blood tests cause epidemiological risks associated with difficulties in identifying the sources of infection.

scholarly journals Genistein Has Antiviral Activity against Herpes B Virus and Acts Synergistically with Antiviral Treatments to Reduce Effective Dose

Viruses ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 499 ◽  
Author(s):  
Julia C. LeCher ◽  
Nga Diep ◽  
Peter W. Krug ◽  
Julia K. Hilliard
Keyword(s):  
Antiviral Activity ◽  
Effective Dose ◽  
Viral Entry ◽  
Therapeutic Potential ◽  
Antiviral Treatment ◽  
Antiviral Agent ◽  
Virus Production ◽  
Macaque Monkey ◽  
B Virus ◽  
Herpes B Virus

Herpes B virus is a deadly zoonotic agent that can be transmitted to humans from the macaque monkey, an animal widely used in biomedical research. Currently, there is no cure for human B virus infection and treatments require a life-long daily regimen of antivirals, namely acyclovir and ganciclovir. Long-term antiviral treatments have been associated with significant debilitating side effects, thus, there is an ongoing search for alternative efficacious antiviral treatment. In this study, the antiviral activity of genistein was quantified against B virus in a primary cell culture model system. Genistein prevented plaque formation of B virus and reduced virus production with an IC50 value of 33 and 46 μM for human and macaque fibroblasts, respectively. Genistein did not interfere directly with viral entry, but instead targeted an event post-viral replication. Finally, we showed that genistein could be used at its IC50 concentration in conjunction with both acyclovir and ganciclovir to reduce their effective dose against B virus with a 93% and 99% reduction in IC50 values, respectively. The results presented here illuminate the therapeutic potential of genistein as an effective antiviral agent against B virus when used alone or in combination with current antiviral therapies.

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 Synthesis and Antiviral Activities of Methylenecyclopropane Analogs with 6-Alkoxy and 6-Alkylthio Substitutions That Exhibit Broad-Spectrum Antiviral Activity against Human Herpesviruses

2013 ◽  
Vol 57 (8) ◽  
pp. 3518-3527 ◽  
Author(s):  
Mark N. Prichard ◽  
John D. Williams ◽  
Gloria Komazin-Meredith ◽  
Atiyya R. Khan ◽  
Nathan B. Price ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Broad Spectrum ◽  
Human Herpesvirus ◽  
Large Set ◽  
Virus Infections ◽  
Hydroxymethyl Group ◽  
Herpes Simplex Viruses ◽  
Varicella Zoster ◽  
Barr Virus ◽  
Human Herpesviruses

ABSTRACTMethylenecyclopropane nucleosides have been reported to be active against many of the human herpesviruses. The most active compound of this class is cyclopropavir (CPV), which exhibits good antiviral activity against human cytomegalovirus (HCMV), Epstein-Barr virus, both variants of human herpesvirus 6, and human herpesvirus 8. CPV has two hydroxymethyl groups on the methylenecyclopropane ring, but analogs with a single hydroxymethyl group, such as the prototypical (S)-synguanol, are also active and exhibit a broader spectrum of antiviral activity that also includes hepatitis B virus and human immunodeficiency virus. Here, a large set of monohydroxymethyl compounds with ether and thioether substituents at the 6 position of the purine was synthesized and evaluated for antiviral activity against a range of human herpesviruses. Some of these analogs had a broader spectrum of antiviral activity than CPV, in that they also inhibited the replication of herpes simplex viruses 1 and 2 and varicella-zoster virus. Interestingly, the antiviral activity of these compounds appeared to be dependent on the activity of the HCMV UL97 kinase but was relatively unaffected by the absence of thymidine kinase activity in HSV. These data taken together indicate that the mechanism of action of these analogs is distinct from that of CPV. They also suggest that they might be useful as broad-spectrum antiherpesvirus agents and may be effective in the treatment of resistant virus infections.

scholarly journals Novel Nucleoside Analogues as Effective Antiviral Agents for Zika Virus Infections

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4813
Author(s):  
Marcella Bassetto ◽  
Cecilia M. Cima ◽  
Mattia Basso ◽  
Martina Salerno ◽  
Frank Schwarze ◽  
...  
Keyword(s):  
Zika Virus ◽  
Antiviral Agents ◽  
Antiviral Agent ◽  
Antiviral Effect ◽  
Health Concern ◽  
Virus Infections ◽  
Direct Acting Antiviral ◽  
Direct Acting ◽  
Further Development

Previously considered a neglected flavivirus, Zika virus has recently emerged as a public health concern due to its ability to spread rapidly and cause severe neurological disorders, such as microcephaly in newborn babies from infected mothers, and Guillain-Barré syndrome in adults. Despite extensive efforts towards the identification of effective therapies, specific antivirals are still not available. As part of ongoing medicinal chemistry studies to identify new antiviral agents, we screened against Zika virus replication in vitro in a targeted internal library of small-molecule agents, comprising both nucleoside and non-nucleoside agents. Among the compounds evaluated, novel aryloxyphosphoramidate prodrugs of the nucleosides 2′-C-methyl-adenosine, 2-CMA, and 7-deaza-2′C-methyl-adenosine, 7-DMA, were found to significantly inhibit the virus-induced cytopathic effect in multiple relevant cell lines. In addition, one of these prodrugs exhibits a synergistic antiviral effect against Zika virus when applied in combination with an indirect antiviral agent, a l-dideoxy bicyclic pyrimidine nucleoside analogue, which potently inhibits vaccinia and measles viruses in vitro by targeting a host pathway. Our findings provide a solid basis for further development of an antiviral therapy for Zika virus infections, possibly exploiting a dual approach combining two different agents, one targeting the viral polymerase (direct-acting antiviral), the second targeting a host-directed autophagy mechanism.

A randomized clinical trial of valacyclovir in multiple sclerosis

2005 ◽  
Vol 11 (3) ◽  
pp. 286-295 ◽  
Author(s):  
J E Friedman ◽  
J B Zabriskie ◽  
C Plank ◽  
D Ablashi ◽  
J Whitman ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Drug Effect ◽  
Brain Mri ◽  
Human Herpesvirus ◽  
Antiviral Agent ◽  
Prolonged Treatment ◽  
High Dose ◽  
Double Blind Study ◽  
Double Blind ◽  
Herpesvirus Type

Objective: The human Herpesvirus type-6 (HHV-6) has been implicated in multiple sclerosis (MS). Valacyclovir is an antiviral agent with an excellent safety profile. A two-year, placebo-controlled, double-blind study was conducted to (1) ascertain if high-dose, prolonged treatment with valacyclovir would be safe and (2) observe if valacyclovir would delay the progression of MS clinically or by magnetic resonance imaging (MRI). Design/methods: Fifty-eight patients were stratified as to severity and randomly assigned to receive valacyclovir (3000 mg/day) or placebo for a period of two years. Patients were followed clinically over the two-year period by means of the Expanded Disability Status Scale (EDSS), the Ambulation Index (AI) and brain MRI scans. Patients underwent routine lab studies every three months. Patients continued on the medication for two years unless they had a sustained progression or repeated exacerbations. Results: No patient discontinued the study due to side effects or toxicity. In Relative Ranking of Progression, time to first attack, attack rate, and time to withdrawal there were trends (but not statistically significant) toward drug effect over placebo in the Severe clinical category. MRI evaluation showed no significant drug effect. Conclusions: Although not statistically significant, positive trends were detected for acyclovir by clinical measures, but not by MRI.

scholarly journals Investigation of monotherapy and combined anticoronaviral therapies against feline coronavirus serotype II in vitro

2021 ◽  
pp. 1098612X2110486
Author(s):  
Sarah E Cook ◽  
Helena Vogel ◽  
Diego Castillo ◽  
Mark Olsen ◽  
Niels Pedersen ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Antiviral Agents ◽  
Clinical Signs ◽  
Treatment Strategies ◽  
Antiviral Effect ◽  
Ocular Involvement ◽  
Virus Infections ◽  
Viral Inhibition ◽  
Antiviral Compounds

Objectives Feline infectious peritonitis (FIP), caused by genetic mutants of feline enteric coronavirus known as FIPV, is a highly fatal disease of cats with no currently available vaccine or US Food and Drug Administration-approved cure. Dissemination of FIPV in affected cats results in a range of clinical signs, including cavitary effusions, anorexia, fever and lesions of pyogranulomatous vasculitis and perivasculitis, with or without central nervous system or ocular involvement. The objectives of this study were to screen an array of antiviral compounds for anti-FIPV (serotype II) activity, determine cytotoxicity safety profiles of identified compounds with anti-FIPV activity and strategically combine identified monotherapies to assess compound synergy against FIPV in vitro. Based upon clinically successful combination treatment strategies for human patients with HIV and hepatitis C virus infections, we hypothesized that a combined anticoronaviral therapy approach featuring concurrent multiple mechanisms of drug action would result in an additive or synergistic antiviral effect. Methods This study screened 90 putative antiviral compounds for efficacy and cytotoxicity using a multimodal in vitro strategy, including plaque bioassays, real-time RT-PCR viral inhibition and cytotoxicity assays. Results Through this process, we identified 26 compounds with effective antiviral activity against FIPV, representing a variety of drug classes and mechanisms of antiviral action. The most effective compounds include GC376, GS-441524, EIDD2081 and EIDD2931. We documented antiviral efficacy for combinations of antiviral agents, with a few examined drug combinations demonstrating evidence of limited synergistic antiviral activity. Conclusions and relevance Although evidence of compound synergy was identified for several combinations of antiviral agents, monotherapies were ultimately determined to be the most effective in the inhibition of viral transcription.

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