Identification of Non-Nucleoside DNA Synthesis Inhibitors of Vaccinia Virus by High-Throughput Screening
| Autor: | Robert P. Ricciardi, Abigail M. Druck Shudofsky, Mihai Ciustea, Janice Elaine Y. Silverman |
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| Rok vydání: | 2008 |
| Předmět: |
viruses
Drug Evaluation Preclinical Vaccinia virus complex mixtures Antiviral Agents Article Virus Cell Line Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Poxviridae Orthopoxvirus Nucleic Acid Synthesis Inhibitors Molecular Structure biology DNA synthesis Chemistry virus diseases Nucleosides biology.organism_classification Virology Chordopoxvirinae Molecular Medicine Variola virus Vaccinia Cidofovir |
| Zdroj: | Journal of Medicinal Chemistry. 51:6563-6570 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm800366g |
| Popis: | Variola virus, the causative agent of smallpox, is a potential bioweapon. The development of new antiviral compounds for smallpox prophylaxis and treatment is critical, especially because the virus can acquire resistance to the drugs that are currently available. We have identified novel small chemical inhibitors that target DNA synthesis of vaccinia, the prototypical poxvirus. Robotic high-throughput screening of 49663 compounds and follow-up studies identified very potent inhibitors of vaccinia DNA synthesis, with IC 50 values as low as 0.5 microM. Cell-based assays showed that 16 inhibitors effectively blocked vaccinia infection with minimal cytotoxicity. Three inhibitors had selectivity indexes that approximate that of cidofovir. These new non-nucleoside inhibitors are expected to interfere with components of the vaccinia DNA synthesis apparatus that are distinct from cidofovir. On the basis of the high sequence similarity between the proteins of vaccinia and variola viruses, these new inhibitors are anticipated to be equally effective against smallpox. |
| Databáze: | OpenAIRE |
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