YM-53403, a unique anti-respiratory syncytial virus agent with a novel mechanism of action
| Autor: | Yasuaki Shimizu, Kenji Sudo, Masafumi Shintani, Naoko Kojima, Yoji Miyazaki, Hiroshi Suzuki, Masayuki Kobayashi |
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| Rok vydání: | 2005 |
| Předmět: |
Cyclopropanes
Genes Viral Paramyxoviridae viruses Microbial Sensitivity Tests Biology Virus Replication medicine.disease_cause Antiviral Agents Virus Cell Line Microbiology Measles virus Viral Proteins chemistry.chemical_compound Dogs Virology Chlorocebus aethiops Drug Resistance Viral medicine Influenza A virus Animals Humans Point Mutation Mononegavirales Vero Cells Cytopathic effect Pharmacology Ribavirin Benzazepines biology.organism_classification Respiratory Syncytial Viruses Herpes simplex virus chemistry HeLa Cells |
| Zdroj: | Antiviral Research. 65:125-131 |
| ISSN: | 0166-3542 |
| Popis: | We performed a large-scale random screening of an in-house chemical library based on the inhibition of respiratory syncytial virus (RSV)-induced cytopathic effect on HeLa (human cervical carcinoma) cells, and found a novel and specific anti-RSV agent, 6-{4-[(biphenyl-2-ylcarbonyl) amino]benzoyl}-N-cyclopropyl-5,6-dihydro-4H-thieno[3,2-d][1]benzazepine-2-carboxamide (YM-53403). YM-53403 potently inhibited the replication of RSV strains belonging to both A and B subgroups, but not influenza A virus, measles virus, or herpes simplex virus type 1. A plaque reduction assay was used to determine the 50% effective concentration (EC(50)) value for YM-53403. The value, 0.20 microM, was about 100-fold more potent than ribavirin. The result of a time-dependent drug addition test showed that YM-53403 inhibited the life cycle of RSV at around 8h post-infection, suggesting an inhibitory effect on early transcription and/or replication of the RSV genome. Consistent with this result, two YM-53403-resistant viruses have a single point mutation (Y1631H) in the L protein which is a RNA polymerase for both the transcription and replication of the RSV genome. YM-53403 is an attractive compound for the treatment of RSV infection because of its highly potent anti-RSV activity and the new mode of action, which differs from that of currently reported antiviral agents. |
| Databáze: | OpenAIRE |
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