The nucleotide phosphonates cidofovir (CDV) and cyclic cidofovir (cCDV) are potent antiviral compounds when administered parenterally but are not well absorbed orally. These compounds have been reported to have activity against orthopoxvirus replication in vitro and in animal models when administered parenterally or by aerosol. To obtain better oral activity, we synthesized a novel series of analogs of CDV and cCDV by esterification with two long-chain alkoxyalkanols, 3-hexadecyloxy-1-propanol (HDP-CDV; HDP-cCDV) or 3-octadecyloxy-1-ethanol (ODE-CDV; ODE-cCDV). Their activities were evaluated and compared with those of CDV and cCDV in human foreskin fibroblast (HFF) cells infected with vaccinia virus (VV) or cowpox virus (CV) using a plaque reduction assay. The 50% effective concentrations (EC 50 s) against VV in HFF cells for CDV and cCDV were 46.2 and 50.6 M compared with 0.84 and 3.8 M for HDP-CDV and HDP-cCDV, respectively. The EC 50 s for ODE-CDV and ODE-cCDV were 0.20 and 1.1 M, respectively. The HDP analogs were 57-and 13-fold more active than the parent nucleotides, whereas the ODE analogs were 231-and 46-fold more active than the unmodified CDV and cCDV. Similar results were obtained using CV. Cytotoxicity studies indicated that although the analogs were more toxic than the parent nucleotides, the selective index was increased by 4-to 13-fold. These results indicate that the alkoxyalkyl esters of CDV and cCDV have enhanced activity in vitro and need to be evaluated for their oral absorption and efficacy in animal models.Since smallpox was considered to be eradicated in the 1970s, there has been little activity in developing antiviral agents for this infection (10). However, in view of the threat of bioterrorism using variola virus or other orthopoxviruses, such as monkeypox virus, which continues to infect humans in central Africa, there is a renewed need to develop antiviral agents for these viruses (3,11,12,17,18,24). For many years the laboratory of Erik De Clercq and other laboratories have utilized in vitro and animal models with vaccinia virus (VV) to screen potential antiviral compounds for activity against poxviruses and have identified a few active agents. Methisazone, ribavirin, idoxuridine, interferon, interferon inducers, S2442, and cidofovir (CDV) have been identified as potential therapies for these infections (7,8,9,20,21,23). Of particular interest was the finding that CDV and other phosphonate nucleotides were inhibitory to this group of viruses, including VV, cowpox virus (CV), camelpox virus, monkeypox virus, and variola virus (J. W. Huggins, personal communication). The activity of CDV is of particular interest as a potential therapy for smallpox, as it is already approved for the treatment of cytomegalovirus (CMV) infections and has been shown to have activity in animal models using VV and CV (2,22,26,27). We have confirmed the activity of CDV against both VV and CV in tissue culture and animal models in our laboratory (4) and report here the results of some new alkoxyalkyl esters o...
The incidence of cytomegalovirus (CMV) retinitis is declining in AIDS patients but remains a significant clinical problem in patients with organ transplants and bone marrow transplants. Prophylaxis with ganciclovir (GCV) or valganciclovir reduces the incidence of CMV disease but may lead to the emergence of drug-resistant virus with mutations in the UL97 or UL54 gene. It would be useful to have other types of oral therapy for CMV disease. We synthesized hexadecyloxypropyl and octadecyloxyethyl derivatives of cyclic cidofovir (cCDV) and cidofovir (CDV) and found that these novel analogs had 2.5-to 4-log increases in antiviral activity against CMV compared to the activities of unmodified CDV and cCDV. Multiple-log increases in activity were noted against laboratory CMV strains and various CMV clinical isolates including GCV-resistant strains with mutations in the UL97 and UL54 genes. Preliminary cell studies suggest that the increase in antiviral activity may be partially explained by a much greater cell penetration of the novel analogs. 1-O-Hexadecyloxypropyl-CDV, 1-O-octadecyloxyethyl-CDV, and their corresponding cCDV analogs are worthy of further preclinical evaluation for treatment and prevention of CMV and herpes simplex virus infections in humans.Although the incidence and prevalence of cytomegalovirus (CMV) retinitis in AIDS patients are declining due to the use of highly active antiretroviral therapies (12), CMV continues to be a major cause of opportunistic infections in patients with allogeneic bone marrow transplants (BMTs) and solid-organ transplants (6). In transplant patients, the incidence of CMV infection increases with the duration and degree of immunosuppression, approximating 70% in allogeneic BMT patients who are CMV seropositive (2) and in patients receiving solidorgan transplants from CMV-seropositive donors (4, 18). CMV disease is associated with a high risk of morbidity and mortality in solid-organ transplant and allogeneic BMT patients (6). While prophylaxis with ganciclovir (GCV) significantly reduces the incidence of CMV disease in transplant recipients, drug resistance may emerge because of mutations in the UL97 gene, which catalyzes the initial phosphorylation of GCV, or in the UL54 polymerase gene of the virus (for a review, see reference 5). Current therapies for CMV disease in transplant patients are based primarily on intravenous therapy with GCV, cidofovir (CDV), or foscarnet (phosphonoformate) or, more recently, with oral valganciclovir.It would be useful to identify more effective oral therapies for the treatment of CMV disease in allogeneic bone marrow, stem cell, or solid-organ transplant patients and in CMV retinitis patients with AIDS. We have developed a strategy to improve the antiviral activity and oral absorption of acyclovir (ACV) and GCV by covalently attaching alkoxyalkyl or alkoxyglyceryl residues to the phosphate of ACV monophosphate or GCV monophosphate (1,8,9). These ether lipid analogs generally show severalfold increases in activity over the activity of underiva...
Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), and human herpesvirus 8 (HHV-8) are responsible for a number of clinical manifestations in both normal and immunocompromised individuals. The parent benzimidazole ribonucleosides evaluated in this series, 2-bromo-5,6-dichloro-1-(-D-ribofuranosyl)benzimidazole (BDCRB) and maribavir (1263W94), are potent and selective inhibitors of human CMV replication. These nucleosides act by two different mechanisms. BDCRB blocks the processing and maturation of viral DNA, whereas 1263W94 inhibits the viral enzyme pUL97 and interferes with DNA synthesis. In the present study, we have evaluated the in vitro antiviral activity of BDCRB, an analog, GW275175X (175X), and 1263W94 against the replication of HSV-1, HSV-2, VZV, CMV, EBV, HHV-6, and HHV-8. By using various methodologies, significant activity was observed against human CMV and EBV but not against HSV-1, HSV-2, VZV, HHV-6, or HHV-8. Plaque reduction assays performed on a variety of laboratory and clinical isolates of human CMV indicated that all strains, including those resistant to ganciclovir (GCV) and foscarnet, were sensitive to all three benzimidazole ribonucleosides, with mean 50% effective concentration values of about 1 to 5 M compared to that of GCV at 6 M. The toxicity of these compounds in tissue culture cells appeared to be similar to that observed with GCV. These results demonstrate that the benzimidazole ribonucleosides are active against human CMV and EBV and suggest that they may be useful for the treatment of infections caused by these herpesviruses.
Herpes simplex virus types 1 and 2 (HSV-1, HSV-2) infections are common, but can cause serious infections in neonates and the immunocompromised. Drugs currently used to treat cutaneous or genital HSV infections are effective in limiting disease, but the emergence of drug resistant viruses in immunocompromised individuals can be problematic. While the prophylactic oral treatment with antiviral drugs can reduce virus shedding and transmission, there is a need for topical microbicides that have the potential to limit sexual transmission of the virus. Previous reports demonstrated the antiviral activity of complex sulfated polysaccharides extracted from various species of marine algae and suggested that they interfered with the attachment of virions to host cells. Here, we evaluated the antiviral activity of extracts from Undaria pinnatifida, Splachnidium rugosum, Gigartina atropurpurea, and Plocamium cartilagineum against HSV-1 and HSV-2. These extracts exhibited good activity when added during the first hour of viral infection, but were ineffective if added later. Plaque reduction assays, when the extracts were added prior to viral inoculation, yielded EC50 values that ranged from 1.5-36 μg/ml for HSV-1 and 0.7-6.6 μg/ml for HSV-2. None of the extracts exhibited significant toxicity in a neutral red uptake assay (IC50 >100 μg/ml). Subsequent assays showed that the compounds had potent virucidal activity and were active at very low concentrations. We conclude that these extracts are nontoxic and effective virucidal agents that warrant further investigation to examine their potential role in the prevention of HSV infections of humans.
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 (EC 50 ) levels of <50 M. Six of the 18 compounds were active against HCMV by cytopathic effect or PR assays with EC 50 s of 0.5 to 44 M, and all were active against MCMV by PR (0.3 to 54 M). Four of the compounds were active against EBV by enzyme-linked immunosorbent assay (<0.3 to 4.4 M). Four compounds with CMV activity were also active against HHV-6A and HHV-6B (0.7 to 28 M), and three compounds were active against HHV-8 (5.5 to 16 M). One of these, ZSM-I-62, had particularly good activity against CMV, HHV-6, and HHV-8, with EC 50 s of 0.7 to 8 M. 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.Human cytomegalovirus (HCMV) infects approximately 40 to 80% of the population, and serious life-threatening manifestations are associated with congenital infection and immunosuppression (5). Currently, therapeutic agents such as ganciclovir (GCV), foscarnet (PFA), and cidofovir (CDV) are used to treat HCMV infections, and while GCV is highly effective in treating CMV retinitis, pneumonia, and gastrointestinal disease, long-term therapy is generally required because infection often recurs upon cessation of therapy. The development of drug resistance and severe side effects due to drug toxicity may also occur during long courses of treatment and may limit the clinical use of these drugs. The increased use of immunosuppression for cancer chemotherapy and organ transplantation presents an ever-increasing need for more effective and less toxic antiviral drugs.A relatively new series of nucleoside analogs, the methylenecyclopropanes were modeled after allene analogs, which have been shown to exhibit antiviral activity (23). The first generation can be regarded as bioisosteric analogs of acyclovir where the C-O-C moiety was replaced by the methylenecyclopropane moiety. In a similar fashion, the second generation of methylenecyclopropane analogs are related to ganciclovir (25). In both cases, the Z-and E-isomeric series of analogs were generated. We have reported previously that ...
Cidofovir (CDV) is an effective therapy for certain human cytomegalovirus (HCMV) infections in immuno-compromised 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), EpsteinBarr virus (EBV), human herpesvirus 6 (HHV-6), and HHV-8. Using several different in vitro assays, concentrations of drug as low as 0.001 M reduced herpesvirus replication by 50% (EC 50 ) with the CDV analogs, whereas the cCDV compounds were generally less active. In most of the assays performed, the EC 50 values of the lipid esters were at least 100-fold lower than the EC 50 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.
bMethylenecyclopropane 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 varicellazoster 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.
The antiviral activity of a new series of thymidine analogs was determined against vaccinia virus (VV), cowpox virus (CV), herpes simplex virus, and varicella-zoster virus. Several compounds were identified that had good activity against each of the viruses, including a set of novel 5-substituted deoxyuridine analogs. To investigate the possibility that these drugs might be phosphorylated preferentially by the viral thymidine kinase (TK) homologs, the antiviral activities of these compounds were also assessed using TK-deficient strains of some of these viruses. Some of these compounds were shown to be much less effective in the absence of a functional TK gene in CV, which was unexpected given the high degree of amino acid identity between this enzyme and its cellular homolog. This unanticipated result suggested that the CV TK was important in the mechanism of action of these compounds and also that it might phosphorylate a wider variety of substrates than other type II enzymes. To confirm these data, we expressed the VV TK and human TK1 in bacteria and isolated the purified enzymes. Enzymatic assays demonstrated that the viral TK could efficiently phosphorylate many of these compounds, whereas most of the compounds were very poor substrates for the cellular kinase, TK1. Thus, the specific phosphorylation of these compounds by the viral kinase may be sufficient to explain the TK dependence. This unexpected result suggests that selective phosphorylation by the viral kinase may be a promising new approach in the discovery of highly selective inhibitors of orthopoxvirus replication.
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