Synergistic Combination Effect of Cidofovir and Idoxuridine on Vaccinia Virus Replication

Abstract

In view of the potential menace of a terrorism attack with smallpox virus, an intensive search of chemotherapeutic agents active against orthopoxviruses is underway. We comparatively studied the antiviral activity of cidofovir (CDV) and idoxuridine (IUdR) against two vaccinia virus (VV) strains, Bratislava and RIIPD, in cell cultures of chick embryo fibroblasts (CEF). The investigations were carried out according to cytopathic effect (CPE) inhibition assay protocols. To determine the cytotoxicity of the compounds, maximal tolerated concentration (MTC) was calculated in CEF cell monolayers and 50% cell growth inhibitory concentration (CGIC 50 ) was calculated in growing cell cultures. It was found that the antiviral effects were strongly dependent on virus inoculum size. There were no marked differences in the susceptibility to CDV and IUdR between the two VV strains. The individual half maximal inhibitory concentration (IC 50 ) for CDV varied from 7.1-8.5 µ µM at 10/100 virus 50% infectious dose (ID 50 ) to 13.6-26.5 µ µM Smallpox (variola) is among the most dangerous and highly contagious viral infections affecting humans. The last natural case in Somalia has marked the end of a successful WHO campaign for smallpox eradication by vaccination on a worldwide scale (Deria et al., 1972;Fenner et al., 1988). As a result, the smallpox virus can only be found in laboratories in Atlanta, Georgia, USA and Novosibirsk, Siberia, Russia. Despite smallpox eradication, infections caused by other members of the poxvirus family are also important for human health. The monkeypox virus can infect humans and occasional cases have been reported in Equatorial Africa (Heiner et al., 1998). Molluscum contagiosum and orf infections occur in immunocompromised patients (Kuhl et al., 2003;Murray, 2004). In addition, it has been highlighted that people not vaccinated with vaccinia virus (VV) could become the target of a potential terrorist attack with smallpox (Mahy, 2003). Therefore, there is a need to renew the search of chemotherapeutical agents active against poxviruses.Poxviruses encode a large number of enzymes including DNA polymerase and thymidine kinase, which are of potential interest as targets for antiviral compounds (Citarella et al., 1972;Kit et al., 1977). The first compound described in the literature was p-amino-benzaldehyde thiosemicarbazone, which Brownlee and Hamre (1951) established inhibited the replication of VV. Bauer and Sadler (1960) found 1-methyl-1H-indole-2,3-dione-3-thiosemicarbazone (methisazone, Marboran ® ) manifested a prophylactic and not a therapeutic effect against smallpox. Later, Borysiewicz et al., (1977) found a comparatively low selectivity ratio value for 1-methyl-1H-indole-2,3-dione-3-thiosemicarbazone based on its marked immunotoxicity. Among compounds showing an anti-poxvirus activity are idoxuridine (IUdR), ribavirin, cidofovir (CDV), interferon and polyacrylic acid (De Clercq, 2001).CDV is an acyclic nucleoside phosphonate licensed for the treatment of cytomegalovirus retinitis in AIDS pat...

Poxviruses: smallpox vaccine, its complications and chemotherapy

“…The data demonstrated clearly defined synergy of the antivirus effect of the combination of cidofovir and idoxuridine, with antagonism of the combined cytotoxicity in a growing and monolayer cell culture. 60 Other compounds are approved for the treatment of poxviruses. The acyclic nucleoside phosphonate drug (S)-9-[3-hydroxy-(2-phosphonomethoxy) propyl]adenine ((S)-HPMPA) is a highly effective inhibitor of vaccinia virus DNA polymerase when incorporated into the template strand.…”

Molecular properties prediction, anticancer and anti-inflammatory activities of some pyrimido[1,2-b]pyridazin-2-one derivatives

“…The pyrimidine pharmacophore occupies an important place in the field of drug development and discovery where a large array of pyrimidine-based compounds with broad-spectrum biological activities was discovered. These include anticancer (5-fluorouracil), 1 antiviral (idoxuridine and trifluoridine), 2 , 3 anti-HIV (zidovudine and stavudine), 4 , 5 antibacterial (trimethoprim, sulphamethazine, sulphadiazine and sulphadoxin), 6 , 7 antimalarial (sulphadoxin), 8 antihypertensive (minoxidil and prazosin), 9 sedative-hypnotic (barbiturates), 10 anticonvulsant (phenobarbitone), 11 antithyroid (propylthiouracil), 12 H1-antihistamine (thonzylamine), 13 and antibiotic drugs (toxoflavin and fervennuline). 14 Regarded as a privileged pharmacophore, the pyrimidine nucleus continues to be explored in the discovery of novel therapeutic agents for diverse clinical applications.…”