Research on substances with activity against orthopoxviruses (original) (raw)
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Antimicrobial Agents and Chemotherapy, 2003
In the event of a bioterrorism attack using smallpox virus, there currently is no approved drug for the treatment of infections with this virus. We have reported previously that ( S )-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (HPMPC) (also known as cidofovir [CDV]) has good activity against poxvirus infections; however, a major limitation is the requirement for intravenous administration. Two related acyclic nucleoside phosphonates (ANPs), adefovir (PMEA) and tenofovir (PMPA), are active against human immunodeficiency virus or hepatitis B virus but do not have activity against the orthopoxviruses. Therefore, we have evaluated a number of analogs and potential oral prodrugs of these three compounds for their ability to inhibit the replication of vaccinia virus or cowpox virus in tissue culture cells. The most-active compounds within the CDV series were ( S )-HPMPA and (butyl l -alaninyl) cyclic HPMPC, with 50% effective concentrations (EC 50 s) from 4 to 8 μM, compared with 33...
New Class of Orthopoxvirus Antiviral Drugs That Block Viral Maturation
Journal of Virology, 2004
By using a homology-based bioinformatics approach, a structural model of the vaccinia virus (VV) I7L proteinase was developed. A unique chemical library of ϳ51,000 compounds was computationally queried to identify potential active site inhibitors. The resulting biased subset of compounds was assayed for both toxicity and the ability to inhibit the growth of VV in tissue culture cells. A family of chemotypically related compounds was found which exhibits selective activity against orthopoxviruses, inhibiting VV with 50% inhibitory concentrations of 3 to 12 M. These compounds exhibited no significant cytotoxicity in the four cell lines tested and did not inhibit the growth of other organisms such as Saccharomyces cerevisiae, Pseudomonas aeruginosa,
Antimicrobial Agents and Chemotherapy, 2002
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
Journal of medicinal …, 2007
Once considered a scourge of mankind, the smallpox (variola) virus has gained notoriety as a potential biological threat. Although mass vaccination remains the primary response by national public health agencies to a terrorist attack using variola virus, concerns over ...
Antiviral Research, 2010
9-(S)-[3-Hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine (HPMPDAP) and its cyclic form were selected for further evaluation as potential drug candidates against poxvirus infections. To increase bioavailability of these compounds, synthesis of their structurally diverse ester prodrugs was carried out: alkoxyalkyl (hexadecyloxypropyl, octadecyloxyethyl, hexadecyloxyethyl), pivaloyloxymethyl (POM), 2,2,2-trifluoroethyl, butylsalicylyl, and prodrugs based on peptidomimetics. Most HPMPDAP prodrugs were synthesized in the form of monoesters as well as the corresponding cyclic phosphonate esters. The activity was evaluated not only against vaccinia virus but also against different herpes viruses. The most potent and active prodrugs against vaccinia virus were the alkoxyalkyl ester derivatives of HPMPDAP, with 50% effective concentrations 400-600-fold lower than those of the parent compound. Prodrugs based on peptidomimetics, the 2,2,2-trifluoroethyl, the POM, and the butylsalicylyl derivatives, were able to inhibit vaccinia virus replication at 50% effective concentrations that were equivalent or ∼10-fold lower than those observed for the parent compounds. a Abbreviations: ANP, acyclic nucleoside phosphonate; bis(POC)-PMPA, bis(isopropyloxycarbonyloxymethyl) ester of 9-(R)-[2-(phosphonomethoxy)propyl]adenine; bis(POM)-PMEA, bis(pivaloyloxymethyl) ester of 9-[2-(phosphonomethoxy)ethyl]adenine; DCC, N,N 0 -dicyclohexylcarbodiimide; HATU, O-7-(azabenzotriazol-1-yl)-N,N,N 0 ,N 0 -tetramethyluronium hexafluorophosphate; HCMV, human cytomegalovirus; HDP-CDV, hexadecyloxypropyl ester of cidofovir; HOBt, 1-hydroxybenzotriazole; HPMPA, 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine; HPMPC, 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (cidofovir); HPMPDAP, 9-(S)-[3-hydroxy-2-(phosphonomethoxy)-
Synergistic combination effect of cidofovir and idoxuridine on vaccinia virus replication
Antiviral chemistry & chemotherapy, 2006
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 (CGIC50) 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 (IC50) for CDV varied from 7.1-8.5 microM at 10/100 virus 50% infe...