Assessing the efficacy of cidofovir against herpesvirus-induced genital lesions in goats using different therapeutic regimens.

Caprine herpesvirus 1 (CpHV-1) infection in goats induces genital vesicular-ulcerative lesions that strictly resemble those produced by human herpesvirus 2 in humans. In previous studies, the potent inhibition of CpHV-1 by cidofovir was demonstrated. Cidofovir antiherpetic activity was evaluated in goats infected experimentally by the vaginal route with CpHV-1 and then treated locally at different times after infection.

Synthesis and anti-CVB 3 evaluation of substituted 5-nitro-2-phenoxybenzonitriles.

The synthesis and SAR of a series of 60 substituted 2-phenoxy-5-nitrobenzonitriles (analogues of MDL-860) as inhibitors of enterovirus replication (in particular of coxsackievirus B3 (CVB 3)) are reported. Several of the analogues inhibited CVB 3 and other enteroviruses at low-micromolar concentrations.

The crystal structure of coxsackievirus B3 RNA-dependent RNA polymerase in complex with its protein primer VPg confirms the existence of a second VPg binding site on Picornaviridae polymerases.

The RNA-dependent RNA polymerase (RdRp) is a central piece in the replication machinery of RNA viruses. In picornaviruses this essential RdRp activity also uridylates the VPg peptide, which then serves as a primer for RNA synthesis. Previous genetic, binding, and biochemical data have identified a VPg binding site on poliovirus RdRp and have shown that is was implicated in VPg uridylation.

Comparative in vitro anti-hepatitis C virus activities of a selected series of polymerase, protease, and helicase inhibitors.

We report here a comparative study of the anti-hepatitis C virus (HCV) activities of selected (i) nucleoside polymerase, (ii) nonnucleoside polymerase, (iii) alpha,gamma-diketo acid polymerase, (iv) NS3 protease, and (v) helicase inhibitors, as well as (vi) cyclophilin binding molecules and (vii) alpha 2b interferon in four different HCV genotype 1b replicon systems.

Suboptimal response to adefovir dipivoxil therapy for chronic hepatitis B in nucleoside-naive patients is not due to pre-existing drug-resistant mutants.

Background: Adefovir dipivoxil (ADV) has demonstrated activity against wild-type and lamivudine-resistant hepatitis B virus (HBV). After 1 year of therapy, a median 3.5-4.

A case for developing antiviral drugs against polio.

Polio eradication is within sight. In bringing the world close to this ultimate goal, the Global Polio Eradication Initiative (GPEI) has relied exclusively on the live, attenuated oral poliovirus vaccine (OPV). However, as eradication nears, continued OPV use becomes less tenable due to the incidence of vaccine associated paralytic poliomyelitis (VAPP) in vaccine recipients and disease caused by circulating vaccine-derived polioviruses (cVDPVs) in contacts.

Arylethynyltriazole acyclonucleosides inhibit hepatitis C virus replication.

Novel acyclic triazole nucleosides with various ethynyl moieties appended on the triazole nucleobase were synthesized efficiently using a convenient one-step Sonogashira reaction in aqueous solution and under microwave irradiation. One of the compounds, 1f, inhibited HCV subgenomic replication with a 50% effective concentration (EC(50)) of 22 microg/ml and did not inhibit proliferation of the host cell at a concentration of 50 microg/ml. A preliminary SAR study suggests that the appended phenyl ring as well as the rigid triple bond linker contributes importantly to the anti-HCV activity.

Potential use of antiviral agents in polio eradication.

In 1988, the World Health Assembly launched the Global Polio Eradication Initiative, which aimed to use large-scale vaccination with the oral vaccine to eradicate polio worldwide by the year 2000. Although important progress has been made, polio remains endemic in several countries. Also, the current control measures will likely be inadequate to deal with problems that may arise in the postpolio era.

Selective inhibitors of picornavirus replication.

Picornaviruses cover a large family of pathogens that have a major impact on human but also on veterinary health. Although most infections in man subside mildly or asymptomatically, picornaviruses can also be responsible for severe, potentially life-threatening disease. To date, no therapy has been approved for the treatment of picornavirus infections.

The thiazolobenzimidazole TBZE-029 inhibits enterovirus replication by targeting a short region immediately downstream from motif C in the nonstructural protein 2C.

TBZE-029 {1-(2,6-difluorophenyl)-6-trifluoromethyl-1H,3H-thiazolo[3,4-a]benzimidazole} is a novel selective inhibitor of the replication of several enteroviruses. We show that TBZE-029 exerts its antiviral activity through inhibition of viral RNA replication, without affecting polyprotein processing. To identify the viral target of TBZE-029, drug-resistant coxsackievirus B3 (CVB3) was selected.

Molecular strategies to inhibit the replication of RNA viruses.

There are virtually no antiviral drugs available for the treatment of infections with RNA viruses. This is particularly worrisome since most of the highly pathogenic and emerging viruses are, and will likely continue to be, RNA viruses. These viruses can cause acute, severe illness, including severe respiratory disease, hemorrhagic fever and encephalitis, with a high case fatality rate.

R75761, a lead compound for the development of antiviral drugs in late stage poliomyelitis eradication strategies and beyond.

In this study the antiviral activity of a panel of 18 out of 240 pyridazinamine analogues was evaluated against the Sabin strains of the three poliovirus types. We found one compound, R75761 which had a comparable 50% effective concentration (EC50) value against all three poliovirus Sabin strains. Virus multiplication was reduced by 10(4.

Inhibition of human immunodeficiency virus type 1 replication in human cells by Debio-025, a novel cyclophilin binding agent.

Debio-025 is a synthetic cyclosporine with no immunosuppressive capacity but a high inhibitory potency against cyclophilin A (CypA)-associated cis-trans prolyl isomerase (PPIase) activity. A lack of immunosuppressive effects compared to that of cyclosporine was demonstrated both in vitro and in vivo. For three cyclosporines, the inhibitory potential against PPIase activity was quantitatively correlated with that against human immunodeficiency virus type 1 (HIV-1) replication.

In Vitro Antiviral Activity of some Novel Isatin Derivatives against HCV and SARS-CoV Viruses.

4-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)amino]-N(4,6-dimethyl-2-pyrimidiny)benzene sulphonamide and its derivatives were evaluated for antiviral activity against Pathogenic viruses such as Hepatitis C Virus and SARS-CoV in Vero and Huh 5-2 cells, respectively. The 5-fluoro derivative inhibited the HCV RNA synthesis at 6 mug/ml, without toxicity at a concentration up to 42 mug/ml in Huh 5-2 cells. Among the compounds tested SPIII-5F exhibits the 45% maximum protection against replication of SARS-CoV in Vero cells.

The VIZIER project: preparedness against pathogenic RNA viruses.

Life-threatening RNA viruses emerge regularly, and often in an unpredictable manner. Yet, the very few drugs available against known RNA viruses have sometimes required decades of research for development. Can we generate preparedness for outbreaks of the, as yet, unknown viruses? The VIZIER (VIral enZymes InvolvEd in Replication) (http://www.

Cross-metathesis mediated synthesis of new acyclic nucleoside phosphonates.

With the commercial availability of well-defined ruthenium metathesis catalysts which combine high stability and broad functional group compatibility, olefin metathesis is now routinely integrated in various syntheses. We will report here the overwhelming power and scope of cross-metathesis in the area of new acyclic nucleoside phosphonates. Scope and limitations of this approach, and especially the E/Z stereocontrol, are discussed on selected examples from our drug discovery group.

Alkyne-azide click chemistry mediated carbanucleosides synthesis.

Hitherto unknown 1,4-disubstituted-[1,2,3]-triazolo-4',4'-dihydroxymethyl-3'-deoxy carbanucleosides were synthesized based on a "click approach." Various alkynes were introduced on a key azido intermediate by the "click" 1,3-dipolar Huisgen cycloaddition. Their antiviral activities and cellular toxicities were evaluated on vaccinia virus.

New analogs of acyclovir substituted at the side chain.

A series of novel analogs of acyclovir, substituted with an alkyl (methyl, ethyl, n-butyl) or phenyl group at the positions 1', 4', and/or 5', has been obtained in a direct one-pot coupling reaction of guanosine and the respective 1,3-dioxolanes. The new acyclonucleosides were essentially inactive in antiviral (HSV, VV, VSV, HBV) evaluation in vitro.

Imidazo[4,5-c]pyridines inhibit the in vitro replication of the classical swine fever virus and target the viral polymerase.

Selective inhibitors of the replication of the classical swine fever virus (CSFV) may have the potential to control the spread of the infection in an epidemic situation. We here report that 5-[(4-bromophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (BPIP) is a highly potent inhibitor of the in vitro replication of CSFV. The compound resulted in a dose-dependent antiviral effect in PK(15) cells with a 50% effective concentration (EC(50)) for the inhibition of CSFV Alfort(187) (subgroup 1.

Synthesis of new benzimidazole-coumarin conjugates as anti-hepatitis C virus agents.

Nineteen new conjugated compounds were successfully synthesized by a one-flask method from benzimidazole and coumarin derivatives. A methylenethio linker was used to connect these two kinds of derivatives. In addition, substituted benzimidazol-2-thiones were also coupled with beta-D-glucose peracetate; the resultant glucosides were further converted to the corresponding 2-(methylthio)coumarin derivatives.

Antiviral treatment of chronic hepatitis B virus infections: the past, the present and the future.

A decade ago, standard therapy against chronic hepatitis B virus infections only consisted of lamivudine or IFN-alpha. Treatment with lamivudine and IFN has been compounded by, respectively, the emergence of drug-resistant virus strains and the appearance of serious side effects. In the last 10 years, hepatitis B treatment has made much progress.

Ester prodrugs of cyclic 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine: synthesis and antiviral activity.

Reaction of 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine (1) with dicyclohexylcarbodiimide and N,N,-dicyclohexyl-4-morpholinocarboxamidine in dimethylformamide at elevated temperature afforded the corresponding cyclic phosphonate 2, that is, 1-{[(5S)-2-hydroxy-2-oxido-1,4,2-dioxaphosphinan-5-yl]methyl}-5-azacytosine. Compound 2 exerts strong in vitro activity against DNA viruses, comparable with activity of parent compound 1. Transformation of 2 to its tetrabutylammonium salt followed by reaction with alkyl or acyloxyalkyl halogenides enabled us to prepare a series of structurally diverse ester prodrugs: alkyl (octadecyl), alkenyl (erucyl), alkoxyalkyl (hexadecyloxyethyl), and acyloxyalkyl (pivaloyloxymethyl) (3-6).

Potent inhibition of genital herpesvirus infection in goats by cidofovir.

Background: Like human herpesvirus 2 (HHV-2) in humans, infection by caprine herpesvirus 1 in goats is associated with genital lesions, and this provides a unique model to study the efficacy and effects of anti-herpetic drugs.

Methods: The antiviral activity of cidofovir was assessed in goats infected experimentally, using various therapeutic protocols.

Results: Topic administration of cidofovir 1% cream prevented the onset of virus-induced genital lesions and drastically reduced virus shedding.

The imidazopyrrolopyridine analogue AG110 is a novel, highly selective inhibitor of pestiviruses that targets the viral RNA-dependent RNA polymerase at a hot spot for inhibition of viral replication.

Ethyl 2-methylimidazo[1,2-a]pyrrolo[2,3-c]pyridin-8-carboxylate (AG110) was identified as a potent inhibitor of pestivirus replication. The 50% effective concentration values for inhibition of bovine viral diarrhea virus (BVDV)-induced cytopathic effect, viral RNA synthesis, and production of infectious virus were 1.2 +/- 0.

Antiviral 2,5-disubstituted imidazo[4,5-c]pyridines: further optimization of anti-hepatitis C virus activity.

Substituted 5-benzyl-2-phenyl-5H-imidazo[4,5-c]pyridines represent a novel class of compounds with activity against pestiviruses and the hepatitis C virus (HCV). Several series of analogues with modifications of the substituents in positions 2 and 5 were prepared. These efforts resulted in the discovery of several compounds with potent antiviral activity of which 2-(2,3-difluorophenyl)-5-[4-(trifluoromethyl)benzyl]-5H-imidazo[4,5-c]pyridine (46) was most potent against HCV (EC(50) of 0.