R Snoeck

..Therefore, efforts have been made in different directions including the exploration of new targets for antiviral chemotherapy, the use of immunomodulators and the development of specific vaccines...

..This agent does not depend on the virus-encoded TK, but on cellular enzymes for its conversion to the diphosphoryl derivative, which then inhibits the viral DNA polymerase...

....

..006). None of the patients in the cidofovir group experienced progression of the disease, compared with 5 (45%) of 11 patients in the placebo group. The side effects recorded for both groups were comparable...

..The present paper describes different approaches for the treatment of HPV lesions, still mostly based on surgery, and underlines the importance of developing adjuvant therapies...

....

..Passive immuniatin based on specific immunoglobulins does not effectively prevent VZV infection and is therefore restricted to high risk individuals (i.e. immunocompromised children and pregnant women)...

..Cidofovir, which is on the market for the treatment of human cytomegalovirus retinitis in immunocompromised patients, is potentially a good candidate for the treatment of a poxvirus outbreak, in the absence of any vaccination...

..Finally, CMV423 combined with either ganciclovir, foscarnet or cidofovir in checkerboard experiments demonstrated a highly synergistic activity...

..The 6-[2-(phosphonomethoxy)alkoxy]-2,4-diaminopyrimidines offer substantial potential for the treatment of a broad range of retro-, hepadna-, herpes-, adeno-, and poxvirus infections...

..The DNA chain-terminating properties of PMEApp and (RS)-FPMPApp seem to be a prerequisite for acyclic nucleoside phosphonates to exhibit antiretrovirus (i.e., anti-HIV) activity...

..The different drug-resistant mutants varied in neurovirulent behaviour, the HPMPC(r) strains showing reduced neurovirulence compared with the wild-type...

....

..The elaidic acid ester of GCV should therefore be considered as a novel approach towards the treatment of HSV infections...

..In addition, upon oral administration to MSV-infected mice, (R)-PMPDAP showed marked antiretroviral efficacy...

..The nucleotide sequences of the DNA polymerase genes of the different mutants was then compared with the nucleotide sequence of the wild-type HSV-1 KOS strain...

..S2242 was found to be a substrate (K(m) = 90 microM) for purified human deoxyguanosine kinase; the latter enzyme was stimulated 3-4-fold in HCMV-infected cells...

....

..The HPMPO-, PMEO- and PMPO-DAPym derivatives represent a novel well-defined subclass among the acyclic nucleoside phosphonates endowed with potent and selective antiviral activity...

..In addition, we describe here that this HSV-1 isolate possesses a unique phenotype and genotype...

..These findings provide a rationale for the use of HPMPC and other ANPs in the treatment of orf (contagious ecthyma) in humans and animals...

....

..Topical cidofovir treatment resulted in complete regression of the lesion. This case is discussed in the context of the known literature on orf (ecthyma contagiosum)...

....

....

..Our data thus indicate that ACV and PCV select in vitro for different drug-resistant VZV phenotypes; whether this is also the situation in vivo remains to be investigated...

..On the contrary, leflunomide, which has also been proposed for the management of BKV-associated diseases, is not able to inhibit BKV replication at nontoxic concentrations...

..Collectively, our antiviral data show that the adenovirus DNA polymerase exhibits sensitivity to a relatively broad spectrum of inhibitors and should be studied further as an antiviral target in antiadenovirus drug development programs...

....

..Our data suggest that the eventual target of the BCNAs against VZV is either absent in SVV or, alternatively, is insensitive for the (phosphorylated) BCNAs...

....

..This is the first case report of systemic use of cidofovir to treat recurrent respiratory papillomatosis...

..In this review we describe the advances on research on 3D epithelial cultures for the study of virus growth and pathogenesis of different families of viruses, including papilloma-, herpes-, pox-, adeno-, and parvoviruses...

..It is believed that the flexibility of the cyclohexene ring is essential for their antiviral activity...

..Lack of cross-resistance against a broad variety of mutant HCMV strains points to an antiviral target that is different from those drugs that are currently approved for clinical use...

..The last class showed the highest activities and selectivities against both polyomaviruses...

..Decomposition of 1 in alkaline solutions resulted in products 17 and 18. While the N-formylguanidine derivative 17 proved active, the carbamyolguanidine derivative 18 was devoid of antiviral activity...

..Furthermore the fluorimetric data could be confirmed by a flow cytometry assay. GFP- and EYFP-recombinant viruses proved to be a convenient tool for the evaluation of antiviral agents...

..Our results support the development of alkoxyalkyl esters of ANPs as antivirals not only for the treatment of complicated human orf lesions, but also in the therapy and prophylaxis of contagious ecthyma in sheep and goats...

..Our studies show that proposed drug therapies offer a reasonable likelihood of controlling orthopoxvirus infections, even if the viruses encode drug resistance markers...

..Currently, there are no effective therapies against smallpox and new treatment strategies are greatly needed...

..Prodrugs were at least 20-fold more active than their parent compounds. Octadecycloxyethyl-(S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine emerged as the most potent derivative...

..We conclude that these arylsulfone derivatives represent new betaherpesvirus inhibitors with a novel mode of action that results in indirect inhibition of viral DNA synthesis...

....

..Interestingly, these studies revealed that the compounds may inhibit HCMV at the DNA polymerase step via a non-nucleoside mechanism...

..This review focuses on non-nucleoside compounds that inhibit specific viral processes and on cell-based approaches that result in the selective inhibition of virus replication...

..However, other factors besides affinity for VZV-TK must account for the greatly reduced antiviral potency...

..To progress the anti-varicella-zoster-virus (VZV) aryl bicyclic nucleoside analogues (BCNAs) to the point of Phase 1 clinical trial for herpes zoster...

..The relative configuration of the diastereoisomer trans-6 was determined using H,H-NOESY NMR...

..Our results demonstrate that compounds belonging to the newly synthesized ANPs, in addition to cidofovir, represent promising candidates for the treatment of poxvirus infections...

....

..These compounds showed similar activity against thymidine kinase competent (TK(+)) and deficient (TK(-)) VZV strains, demonstrating a mechanism of action independent of the viral thymidine kinase...

..Scope and limitations of this approach, and especially the E/Z stereocontrol, are discussed on selected examples from our drug discovery group...

..It appears that drug-resistant mutants arising under the pressure of HPMP derivatives have the lowest levels of neurovirulence...

....

..This group of 5-alkynylarabino/deoxy-uridines showed an enhanced ability to inhibit cells transfected with a viral thymidine kinase gene (HSV-1tk+, HSV-2tk+, VZVtk+) relative to wild-type or thymidine kinase-deficient (tk-) cells...

..Unlike the parent nucleoside these novel phosphate prodrugs retain antiviral potency versus the ACV-resistant virus strain, suggesting an efficient bypass of the viral thymidine kinase...

..Since no animal model is available for the evaluation of antiviral agents against VZV, the organotypic cultures may be considered a model to evaluate the efficacy of new anti-VZV antivirals before clinical trials...

..While the alkyl chain analogues were shown to retain full antiviral activity against VZV, these new analogues did not when compared to their furo parent nucleosides...

..They represent new leads in the discovery of improved therapies for HCMV, particularly in view of their novel mechanism of action...

..We, therefore, conclude that CMV423 exerts its activity against HHV-6 through inhibition of a cellular process that is critical at early stages of viral replication and that may affect protein tyrosine kinase activity...

..We found that 1-benzyl-3-(3,5-dimethylbenzyl)uracil and 1-cyanomethyl-3-(3,5-dimethylbenzyl)-4-thiouracil showed powerful inhibition against HCMV and HIV-1, respectively...

..Uniquely amongst compounds of this family to date the present agents show dual anti- (VZV) and human cytomegalovirus (HCMV) activity. The lead compounds inhibit VZV at 10 nM and HCMV at 5 microM...

..0023-0.0110 mumol/mL), comparable to that of the reference drugs adefovir and tenofovir, but were devoid of measurable toxicity at 0.3 mumol/mL...

..The results presented here suggest that compound 10 should be considered as a new lead in the development of antiviral agents...

..The p-fluorophenyl compound is unique amongst compounds of this class in being inactive as an antiviral. The possible origins of these marked SARs are discussed...

..The antiviral activity against human cytomegalovirus (HCMV) was investigated. It was strongly influenced by the nature of C-2 substituent...

..As iron may participate in the pathogenesis of viral infections and cancer in several ways, the present study was designed to investigate the effect of iron chelation on HPV-16- and HPV-18-positive cervical carcinoma cell lines...

..Three of the four patients had a complete response. The fourth patient showed a clinical response in the first cycle of treatment, but new lesions appeared during four successive cycles of cidofovir...

..In analogy to N(9)-[2-(phosphonomethoxy)propyl]-2,6-diaminopurine (PMPDAP), solely the (R)-2,4-diamino-6-[2-(phosphonomethoxy)propoxy]pyrimidine exerted antiviral activity, whereas its (S)-enantiomer was essentially inactive...

..Even before viremia is present, an important rise in the urinary viral load should draw the attention of the transplant clinician and raise the issue of adapting the immunosuppression...

..This is the first report where a complete cure of the lung lesions occurred in a child, and was sustained for at least 24 months...

..Mutant virus strains selected in the presence of the BCNAs were solely cross-resistant to drugs, such as ACV and BVDU, that depend for their antiviral action on metabolic activation by the viral thymidine kinase...

..The A168T change, associated with an altered TK phenotype, proved to be the most commonly selected substitution. For the different mutants, a correlation between phenotype, genotype, and in vivo neurovirulence was observed...

..This led to low micromolar inhibitors of HCMV replication, with 17 and 27 being particularly promising lead compounds for further investigation, although their toxicity still needs to be lowered...

..This has never been observed previously for TSAO derivatives. In particular, compound 26 represents the first TSAO derivative with dual anti-HIV-1 and -HCMV activity...

..In this selected group of recipients with BKVIN, the use of adjuvant low-dose cidofovir therapy resulted in prolonged graft survival and stabilized graft function...

..2d and 2f showed modest, albeit selective, activity against cytomegalovirus (2d, EC50 = 7.3-8.9 microg mL(-1), selectivity index 7-10; 2f, EC50 = 7-13 microg mL(-1), selectivity index 10)...

..We now find that the fully deoxygenated 2',3',5'-trideoxy analogue is fully antivirally active. This is taken as proof that these agents act by a novel non-nucleoside mechanism of action...

..Certain of the long-chain analogues showed activity against VZV and HCMV. No significant activity against other DNA and RNA virus replication or against tumor cell proliferation was observed...

..These results confirm free 5'-OH and 3'-OH as necessary requirements for efficient recognition by VZV TK and for potent anti-VZV activity in cell culture...

..Local cidofovir therapy for viral hemorrhagic cystitis could be an alternative to intravenous administration of cidofovir...

....

..Whether this difference in structure can be correlated with the biological activity will be investigated in future studies...

..8 and 3.8 microM, respectively, for compounds 3 and 9) at a approximately 5-fold lower concentration than that required to show cytotoxicity...

..The compound has been shown to inhibit the release of extracellular virus by targeting the F13L W protein and to protect mice from W, CPV and ECTV orthopoxvirus-induced disease...

..The compounds are tested against a range of herpes viruses and display poor activity, strongly supporting the notion of the importance of the presence of a 3'-OH for antiviral activity...

..Interestingly, removal of the carbonyl group of the beta-lactam ring, most likely acting as the serine trap, resulted in an azetidine derivative with anti-HCMV activity comparable to that of the reference compound ganciclovir...

..Its Z-isomer 7 showed highly specific antiproliferative activity against Hep G2 (IC(50)=18microM) and no cytotoxicity to WI 38. Moreover, compounds 3, 4 and 14 expressed some marginal inhibitory activity against HIV-1 and HIV-2...