Substituted benzimidazoles with nanomolar activity against respiratory syncytial virus
| Autor: | Marc Moeremans, Koen Andries, Philip R. Wyde, Rudy Edmond Willebrords, Janssens Frans Eduard, Cois Sommen, Tom Valerius Josepha Gevers, Jean Fernand Armand Lacrampe |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2003 |
| Předmět: |
Paramyxoviridae
viruses DNA Mutational Analysis Viral Plaque Assay Mumps virus Biology medicine.disease_cause Antiviral Agents Respirovirus Virus Cell Fusion Measles virus Multiplicity of infection Cytopathogenic Effect Viral Virology Drug Resistance Viral medicine Humans Point Mutation Rubulavirus Mononegavirales Cytopathic effect Pharmacology biology.organism_classification Respiratory Syncytial Viruses Molecular Weight Morbillivirus Cytokines Benzimidazoles Metapneumovirus Viral Fusion Proteins HeLa Cells |
| Zdroj: | Antiviral research |
| ISSN: | 0166-3542 |
| Popis: | A cell-based assay was used to discover compounds inhibiting respiratory syncytial virus (RSV)-induced fusion in HeLa/M cells. A lead compound was identified and subsequent synthesis of >300 analogues led to the identification of JNJ 2408068 (R170591), a low molecular weight (MW 395) benzimidazole derivative with an EC(50) (0.16 nM) against some lab strains almost 100,000 times better than that of ribavirin (15 microM). Antiviral activity was confirmed for subgroup A and B clinical isolates of human RSV and for a bovine RSV isolate. The compound did not inhibit the growth of representative viruses from other Paramyxovirus genera, i.e. HPIV2 and Mumps Virus (genus Rubulavirus), HPIV3 (genus Respirovirus), Measles virus (genus Morbillivirus) and hMPV. Efficacy in cytopathic effect inhibition assays correlated well with efficacy in virus yield reduction assays. A concentration of 10nM reduced RSV production 1000-fold in multi-cycle experiments, irrespective of the multiplicity of infection. Time of addition studies pointed to a dual mode of action: inhibition of virus-cell fusion early in the infection cycle and inhibition of cell-cell fusion at the end of the replication cycle. Two resistant mutants were raised and shown to have single point mutations in the F-gene (S398L and D486N). JNJ 2408068 was also shown to inhibit the release of proinflammatory cytokines IL-6, IL-8 and Rantes from RSV-infected A549 cells. |
| Databáze: | OpenAIRE |
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